TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*3.A.3.1.1









Na+-, K+-ATPase (Na+ efflux; K+ uptake).  Mutations in the γ-subunit causes renal hypomagnesemia, associated with hypocalciurea (Cairo et al., 2008). The Na/K-ATPase is an important signal transducer that not only interacts and regulates protein kinases, but also functions as a scaffold (Li and Xie, 2009). Capsazepine, a synthetic vanilloid, converts the Na, K-ATPase to a Na-ATPase (Mahmmoud, 2008a). There are alternative α- and β-subunits, α1, α2,... β1, β2,... in muscle which form α1β1, α1β2, α2β1 and α2β2, heterodimers, each with differing Na+ affinities (4-13mM) (Kristensen and Juel, 2010). α3 and β3 isoforms have also been identified. The γ-subunit is the same as TC# 1.A.27.2.1. Poulsen et al. (2010) have proposed a second ion conduction pathway in the C-terminal part of the ATPase. The two C-terminal tyrosines stabilize the occluded Na/K pump conformations containing Na or K ions (Vedovato and Gadsby, 2010). Na+, K+-ATPase mutations causing familial hemiplegic migraines type 2 (FHM2) inhibit phosphorylation (Schack et al., 2012). Salt, the vascular Na+/K+ ATPase and the endogenous glycosides, ouabain and marinobufagenin, play roles in systemic hypertension (Hauck and Frishman, 2012). Protein kinase A (PKA) phosphorylation of Ser936 (in the intracellular loop between transmembrane segments M8 and M9) opens an intracellular C-terminal water pathway leading to the third Na+-binding site (Poulsen et al., 2012). PKA-mediated phosphorylation regulates activity in vivo. Ser-938 is located (Einholm et al. 2016). E960 on the Na+-K+-ATPase and F28 on phospholemman (PLM) are critical for phospholemman (PLM) inhibition, but there is at least one additional site that is important for tethering PLM to the ATPase. Mutations in the Na+/K+-ATPase α3 subunit gene (ATP1A3) cause rapid-onset dystonia-parkinsonism, a rare movement disorder characterized by sudden onset of dystonic spasms and slow movements (Doğanli et al. 2013).  The 3-d strcuture of the Na+-bound Na+,K+-ATPase at 4.3 Å resolution reveals the positions of the three Na+ ions (Nyblom et al. 2013).  Mutations cause adrenal hypertension (Kopec et al. 2014) as well as alternating hemiplegia of childhood (AHC) and rapid-onset dystonia- parkinsonism (RDP) (Rosewich et al. 2014).  Differences in the structures of the ouabain-, digonxin- and bufalin-bound enzyme have been reported (Laursen et al. 2015).  ATPase inhibitors have been shown to be effective anti-cancer agents (Alevizopoulos et al. 2014). Cys45 in the β-subunit can be glutathionylated, regulating the activity of the enzyme (Garcia et al. 2015). ATP1A2 mutations play a role in migraine headaches (Friedrich et al. 2016). The beta2 subunit is essential for motor physiology in mammals, and in contrast to beta1 and beta3, beta2 stabilizes the Na+-occluded E1P state relative to the outward-open E2P state (Hilbers et al. 2016). Numerous transcription factors, hormones, growth factors, lipids, and extracellular stimuli as well as epigenetic signals modulate the transcription of Na,K-ATPase subunits (Li and Langhans 2015). Čechová et al. 2016 have identified two cytoplasmic pathways along the pairs of TMSs, TMS3/TMS7 or TM6S/TMS9 that allow hydration of the cation binding sites or transport of cations from/to the bulk medium. Dissipation of the transmembrane gradient of K+ and Na+ due to ouabain inhibition increases Ptgs2 and Nr4a1 transcription by increasing Ca2+ influx through L-type Ca2+ channels that, in turn, leads to CaMKII-mediated phosphorylation of CREB and calcineurin-mediated dephosphorylation of NFAT, respectively (Smolyaninova et al. 2017). ZMay play a role in the development of gastric adenocarcinomas (Wang et al. 2017). Mutations F785L and T618M give rise to familial rapid onset dystonia parkonsonism by distinct mechanisms (Rodacker et al. 2006). Reacts with methylglyoxal to inhibit its activity (Svrckova et al. 2017).  Accumulation of beta-amyloid (Abeta) at the early stages of Alzheimer's disease is accompanied by reduction of Na,K-ATPase functional activity. Petrushanko et al. 2016 showed that monomeric Abeta(1-42) forms a tight (Kd of 3 mμM), enthalpy-driven equimolar complex with alpha1beta1 Na,K-ATPase. Complex formation results in dose-dependent inhibition of the enzyme hydrolytic activity. The binding site of Abeta(1-42) is localized in the """"gap"""" between the α- and β-subunits of Na,K-ATPase, disrupting the enzyme functionality by preventing the subunits from shifting towards each other. Interaction of Na,K-ATPase with exogenous Abeta(1-42) leads to a pronounced decrease of the enzyme transport and hydrolytic activities and Src-kinase activation in neuroblastoma cells SH-SY5Y. This interaction allows regulation of Na,K-ATPase activity by short-term increases in the Abeta(1-42) level (Petrushanko et al. 2016). Two distinct phospholipids bind to two distinct sites on the ATPase, affecting activity and stability (Habeck et al. 2017). Five cysteinyl residues (C452, C456, C457, C577, and C656) serve as the cisplatin binding sites on the cytoplasmic loop connecting transmembrane helices 4 and 5 (Šeflová et al. 2018).

Eukaryota
Metazoa
3 component systems:
Na+-, K+-ATPase from α, β, γ heterotrimer of Homo sapiens
α1 (ATP1A1) (P05023)
α2 (ATP1A2) (P50993)
α3 (ATP1A3) (P13637)
β1 (ATP1B1) (P05026)
β2 (ATP1B2) (Q58I19)
β3 (ATP1B3) (P54709)
γ1 (ATP1G1) (P54710)
*3.A.3.1.2









H+-, K+-ATPase (gastric; H+ efflux; K+ uptake). Two H3O+ may be transported per ATP hydrolyzed.  Howeve, a cryo-electron microscope structure suggests that 1 H+ and 1 K+ are transporter per ATP hydrolyzed, providing the energy needed to generate the one million fold H+ concentration gradient effected by this enzyme (Abe et al. 2012).  The detailed mechanism has been discussed, and the roles of essential residues have been proposed (Shin et al. 2011).  A number of inhibitors of acid secretion have been identified, and these are of pharmacological importance (Shin et al. 2011). The catalytic alpha subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of TMSs 4, 5, 6 and 8. The beta subunit has one TMS with the N terminus in the cytoplasm. The extracellular domain of the beta subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for enzyme assembly, maturation and sorting (Shin et al. 2009).

Eukaryota
Metazoa
Gastric H+-, K+-ATPase from Homo sapiens
*3.A.3.1.3









Na+-ATPase
Eukaryota
Raphidophyceae
Na+-ATPase (HANA) of Heterosigma akashiwo
*3.A.3.1.4









Non-gastric H+-, K+- or NH4+-ATPase (Swarts et al., 2005; Worrell et al., 2008)

Eukaryota
Metazoa
H+-, K+ or NH4+-ATPase of Rattus norvegicus (P54708)
*3.A.3.1.5









Putative spirochete Na+, K+-ATPase, Lbi6 (1046 aas) (K. Hak & M.H. Saier)
Bacteria
Spirochaetes
Lbi6 of Leptospira biflexa (B0SMV3)
*3.A.3.1.6









Spiny dogfish Na+,K+-ATPase (3-d structure solved at 2.4 Å resolution, Shinoda et al., 2009). The α-subunit is 88% identical to the human Na+,K+ ATPase (TC# 3.A.3.1.1).

Eukaryota
Metazoa
Na+,K+-ATPase α, β, and γ subunits of Squalus acanthias
α (1028aas; Q4H132)
β (305aas; C4IX13)
γ (94aas; Q70Q12)
*3.A.3.1.7









H+/K+-ATPase α-subunit (1534aas) (Ramos et al., 2011)

Eukaryota
Fungi
H+/K+ ATPase of Aspergillus oryzae (Q2U3D2)
*3.A.3.1.8









Putative Na+/K+-ATPase, Mhun_0636 (encoded in an operon with two half sized TrkA homologues, Mhun_0637 and Mhun_0638, that together may regulate the ATPase)

Archaea
Euryarchaeota
Mhun_0636-8 of Methanospirillum hungatei
Mhun_0636 (Q2FLJ9) Mhun_0637 (Q2FLJ8) Mhun_0638 (Q2FLJ6)
*3.A.3.1.9









Ouabain-insensitive K+-independent Na+-ATPase ɑ-subunit, AtnA; very similar to the human ɑ-1 chain of the Na+,K+-ATPase (3.A.3.1.1) (Rocafull et al., 2011).

Eukaryota
Metazoa
AtnA of Cavia porcellus (B3SI05)
*3.A.3.1.10









Putative archaeal Na+, K+ ATPase, Mac8 (encoded with methylcobalamin: coenzyme M methyltransferase; methanol-specific, a metal chaparone protein and an electron transfer protein) (Chan et al., 2010).

Archaea
Euryarchaeota
Putative Na+/K+ ATPase of Methanosarcina acetivorans (Q8THY0)
*3.A.3.1.11









Na+,K+-ATPase α2 subunit, ATP1a2a or ATPA2A. Deficiency causes brain ventricle dilation and embryonic motility in zebra fish. Is essential for skeletal and heart muscle function (Doganli et al. 2012).

Eukaryota
Metazoa
ATPA2 of Danio rerio (Q90X34)
*3.A.3.1.12









Na+,K+-ATPase subunits α (837 aas) and β (302 aas) of the blood fluke ().

Eukaryota
Metazoa
Na+,K+-ATPase subunits α and β of Schistosoma mansoni
alpha, G4VGA0
beta, G4VTH6
*3.A.3.1.13









Na+/K+-ATPase, ATP12A or ATP1AL1 of 1039 aas.  Plays a role in myocardial relaxation (Knez et al. 2014).  Also functions in airway surface liquid acidification which impaires airway host defenses in cells lacking or compromised for CFTR (3.A.1.202.1) (Shah et al. 2016).

Eukaryota
Metazoa
ATP12A of Homo sapiens
*3.A.3.1.14









Na+/K+-ATPase of 1227 aas and 10 TMSs. Involved in cell signaling, volume regulation, and maintenance of electrochemical gradients (Morrill et al. 2016).

Bacteria
Firmicutes
ATPase of Paramecium tetraurelia
*3.A.3.2.1









Plasma membrane Ca2+-ATPase (efflux), PMCA4 (Giacomello et al. 2013).  The CD147 immunosupression protein interacts via its immunomodulatory domains with PMCA4 to bypass T-cell receptor proximal signaling and inhibit interleukin-2 (IL-2) expression (Supper et al. 2016). Deletion of residues 300 - 349, corresponding the the residues deleted in a natural splice variant (de Tezanos Pinto and Adamo 2006).

Eukaryota
Metazoa
Plasma membrane Ca2+-translocating ATPase, PMCA4, of Homo sapiens (P23634)
*3.A.3.2.2









Ca2+-ATPase, Pmc1 (uptake into vacuoles) (Espeso 2016).

Eukaryota
Fungi
Vacuolar membrane Ca2+-translocating ATPase from Saccharomyces cerevisiae Pmc1
*3.A.3.2.3









Ca2+-ATPase, Pmr1 (efflux) (also transport Mn2+ and Cd2+) (Lauer et al., 2008)

Eukaryota
Fungi
Golgi Ca2+-ATPase Pmr1 of Saccharomyces cerevisiae
*3.A.3.2.4









Ca2+-ATPase of 905 aas and 10 TMSs, Pma1

Bacteria
Cyanobacteria
Putative Ca2+-ATPase of Synechocystis sp. pMA1
*3.A.3.2.5









The Golgi Ca2+, Mn2+-ATPase, hSPCA1, ATP2C1 or Hussy-28 (efflux) (the Hailey-Hailey disease protein). Involved in responses to Golgi stress, apoptosis and midgestational death (Okunade et al., 2007). SPCA1 transports Mn2+ from the cytosol into the Golgi. Increasing Golgi Mn2+ transport increased cell viability upon Mn2+ exposure, supporting a role in the management of Mn2+ -induced neurotoxicity (Mukhopadhyay and Linstedt, 2011).

Eukaryota
Metazoa
hSPCA1 of Homo sapiens
*3.A.3.2.6









Ca2+, Mn2+- ATPase (efflux)
Eukaryota
Fungi
Pmr1 of Neurospora crassa
*3.A.3.2.7









The sarco/endoplasmic reticulum Ca2+ -ATPase, SERCA2b or ATP2A2 is encoded by the ATP2A2 gene.  Mutatioins give rise to Darier''s disease; the spectrum of mutations have been related to patients' phenotypes (Ahn et al., 2003; Godic et al. 2010).  SERCA1 functions as a heat generator in mitochondria of brown adipose tissue (de Meis et al., 2006). It normally functions as a Ca2+:H+ antiporter (Karjalainen et al., 2007). Capsaicin converts SERCA to a Ca2+ non-transporting ATPase that generates heat, and is thus a natural drug that augments uncoupled SERCA, resulting in thermogenesis (Mahmmoud, 2008b). Oligomeric interactions of the N-terminus of sarcolipin with the Ca-ATPase have been documented (Autry et al., 2011), and these interactions uncouple ATP hydrolysis from Ca2+ transport (Sahoo et al. 2015) resulting in thermogenesis.  TMS 11, absent in SERCA1a and SERCA2a, functions in regulation (Gorski et al. 2012). The bovine SERCA has also been crystallized (2.9Å resolution; Sacchetto et al., 2012).  These enzymes are regulated differentially by phospholamban (PLN; 1.A.50.1.1) and sarcolipin (SLN; 1.A.50.2.1) as noted above (Gorski et al. 2013).  SERCA2 is regulated by TMEM64 (9.B.27.5.1), a 380 aa 6 TMS membrane protein of the DedA family (TC# 9.B.27) which regulates Ca2+ oscillations by direct interaction with CIRCA2, modulating its activity and influencing osteoblast differentiation (Kim et al. 2013).  Animal SERCAs are inhibited by three short single (C-terminal) TMS membrane proteins, phospholamban (TC# 1.A.50.1), sarcolipin (1.A.50.2) and myoregulin (1.A.50.3), and the inhibitory actions of these peptides on SERCA are counteracted by a peptide called DWORF (Dwarf ORF) (Nelson et al. 2016; Anderson et al. 2015). Small ankyrin 1 (sAnk1; TC#8.A.28.1.2) and sarcolipin (TC# 1.A.50.2.1) interact in their transmembrane domains to regulate SERCA (Desmond et al. 2017).

Eukaryota
Metazoa
SERCA2b of Homo sapiens (P16615)
*3.A.3.2.8









Ca2+-ATPase (efflux) with broad Ca2+ dependence (3.2-320 μm).  Probably inhibited by cipargamin and SJ1733 (Meier et al. 2018).

Eukaryota
Apicomplexa
PfATPase4 of Plasmodium falciparum
*3.A.3.2.9









Ca2+,Mn2+-ATPase, hSPCA2 (ATP2C2) (efflux). 64% identical to hSPCA1 (TC #3.A.3.2.5) but lower affinity for Ca2+ and more restricted tissue distribution (brain and testis); present in the trans-Golgi network. May function in Mn2+ detoxification (Xiang et al., 2005).
Eukaryota
Metazoa
hSPCA2 of Homo sapiens (NP_055676)
*3.A.3.2.10









The autoinhibited, calmodulin-binding Ca2+-ATPase, isoform 8, ACA8 (Baekgaard et al., 2006)
Eukaryota
Viridiplantae
ACA8 of Arabidopsis thaliana (Q9LF79)
*3.A.3.2.11









Plastid Envelope Ca2+ ATPase, PEA1 (lacks a C-terminal calmodulin domain)
Eukaryota
Viridiplantae
PEA1 of Arabidopsis thaliana
(Q37145)
*3.A.3.2.12









Endomembrane plasma membrane-type Ca2+ ATPase, ACA2 (Arabidopsis Ca2+ ATPase isoform 2) (lacks a C-terminal calmodulin domain, but activity is stimulated 5x by calmodulin which binds to an N-terminal inhibitory domain (Harper et al., 1998; Kamrul Huda et al. 2013).

Eukaryota
Viridiplantae
ACA2 of Arabidopsis thaliana
(O81108)
*3.A.3.2.13









Endoplasmic reticular (ER)-type Ca2+/Mn2+ ATPase, ECA1; 80% identical to and orthologous to the Medicago truncatula MCA8 protein of 1081 aas (F9W2W4).

Eukaryota
Viridiplantae
ECA1 of Arabidopsis thaliana
(P92939)
*3.A.3.2.14









Autoinhibited Ca2+ ATPase (ACA9) (expressed in pollen plasma membrane and required for male fertility), calmodulin-binding (Schiøtt et al., 2004).

Eukaryota
Viridiplantae
ACA9 of Arabidopsis thaliana
(Q9LU41)
*3.A.3.2.15









Plasma membrane Ca2+ ATPase, Mca1 (Kraev et al., 1999)
Eukaryota
Metazoa
Mca1 of Caenorhabditis elegans
(O45215)
*3.A.3.2.16









Golgi Ca2+, Mn2+ ATPase, PMR1 (Van Baelen et al., 2001). (The human orthologue ATP2Cl, TC#3.A.3.2.5, causes Hailey-Hailey disease.)
Eukaryota
Metazoa
PMR1 of Caenorhabditis elegans
(Q9XTG4)
*3.A.3.2.17









Intracellular (contractile vacuole) Ca2+ ATPase, PatA (lacks the C-terminal calmodulin domain of most plasma membrane Ca2+ ATPases) (Moniakis et al., 1995)
Eukaryota
Dictyosteliida
PatA of Dictyostelium discoideum
(P54678)
*3.A.3.2.18









The acidocalcisome (vacuole) Ca2+/H+ ATPase TgA1 (involved in Ca2+ homeostasis, vacuolar polyphosphate storage and virulence) (Luo et al., 2005).
Eukaryota
Apicomplexa
TgA1 of Toxoplasma gondii
(Q9N694)
*3.A.3.2.19









Endomembrane (Golgi) Ca2+/Mn2+-ATPase, ECA3 (one of 4 close paralogues in A. thaliana (Mills et al., 2008; Kamrul Huda et al. 2013)

Eukaryota
Viridiplantae
ECA3 of Arabidopsis thaliana (Q0WP80)
*3.A.3.2.20









Putative Ca2+ ATPase Cac1 (possible pseudogene?)
Bacteria
Firmicutes
Cac1 of Clostridium acetobutylicum (Q97JK5)
*3.A.3.2.21









Putative Ca2+ ATPase, Pmo1
Bacteria
Thermotogae
Pmo1 of Petrotoga mobilis (A9BJX0)
*3.A.3.2.22









Putative Ca2+ ATPase, Sth1
Bacteria
Firmicutes
Sth1 of Streptococcus thermophilus (Q5M0A4)
*3.A.3.2.23









Putative Ca2+ ATPase most similar to Golgi Ca2+ ATPases of eukaryotes

Archaea
Euryarchaeota
Putative Ca2+ ATPase of Methanococcus vannielii (A6URW9)
*3.A.3.2.24









Putative Ca2+-ATPase (48% identical to 3.A.3.2.23) (like Golgi Ca2+-ATPases of eukaryotes)

Bacteria
Aquificae
Putative Ca2+-ATPase of Aguifex aeolicus (O66938)
*3.A.3.2.25









Plasma membrane Ca2+-ATPase, isoform 1a (PMCA1) (78% identical to PMCA4 (TC# 3.A.3.2.1)). Maitotoxin converts it into a Ca2+-permeable nonselective cation channel (Sinkins et al., 2009). The C-terminal tail contains most of the regulatory sites including that for calmodulin. The pump is also regulated by acidic phospholipids, kinases, a dimerization process, and numerous protein interactors. In mammals, four genes code for the four basic isoforms. Isoform complexity is increased by alternative splicing of primary transcripts. Pumps 2 and 3 are expressed preferentially in the nervous system (Calì et al. 2017).

Eukaryota
Metazoa
PMCA1 of Homo sapiens (P20020)
*3.A.3.2.26









The M535L virus Ca2+/Mn2+ efflux pump (transcribed during viral infection) (Bonza et al., 2010)

Viruses
Phycodnaviridae
M535L Ca2+ pump of Paramecium bursaria chlorella virus, MT325 (A7IUR5)
*3.A.3.2.27









Plasma Membrane Ca2+-type ATPase, NCA-2 (most like 3.A.3.2.2) (Bowman et al., 2011).

Eukaryota
Fungi
NCA-2 of Neurospora crassa (Q9UUY2)
*3.A.3.2.28









The probable Mg2+/Ca2+ ATPase antiporter (catalyzes Mg2+ uptake and Ca2+ efflux in a single coupled step; Neef et al. 2011)

Bacteria
Firmicutes
Antiporter of Streptococcus pneumoniae (Q04JJ5)
*3.A.3.2.29









The putative Ca+ ATPase with an extra C-terminal TMS followed by a lysin (LysM) domain of ~210aas. LysM domains are often found in cell wall degradative enzymes and have peptidoglycan binding sites. Found in Nitrosococcus oceani as well as Nitrosococcus halophilus. The ATPase domain is 46% identical to 3.A.3.2.4.

Bacteria
Proteobacteria
Putative Ca2+ ATPase of Nitrosococcus  halophilus (D5C355)
*3.A.3.2.30









Pleasma membrane Ca2+-ATPase of parenchymal tissue of the liver fluke, PMCA.  Interacts with a calmodulin-like protein, FhCaM1 in a calcium ion dependent fashion (Moore et al. 2012).

Eukaryota
Metazoa
PMCA of Fasciola helpatica
*3.A.3.2.31









Sarcoplasmic reticulum Ca2+ ATPase, Atp6.  The inhibitors, artemisinin and its anti-malarial derivatives, artesunate and artemether, bind to a hydrophobic pocket in a transmembrane region near the membrane surface (Naik et al. 2011; Meier et al. 2018). Other inhibitors include arterolane and thapsigargin (Meier et al. 2018).

Eukaryota
Apicomplexa
Atp6 of Plasmodium falciparum
*3.A.3.2.32









Lobster intracellular SERCA Ca2+ ATPase of 1020 aas.  In related species, expression of the gene is increased under hypersaline conditions, and the enzyme is ivolved in salinity stress adaptation (Wang et al. 2013).

Eukaryota
Metazoa
ATPase of Palinurus argus
*3.A.3.2.33









Crustacian plasma membrane calcium ATPase of 1170 aas (Chen et al. 2013).

Eukaryota
Metazoa
Calcium ATPase of Callinectes sapidus (blue crab)
   
*3.A.3.2.34









Ca2+/Mn2+-exporting ATPase, Pmr1 of 899 aas (Furune et al. 2008).

Eukaryota
Fungi
Pmr1 of Schizosaccharomyces pombe
*3.A.3.2.35









Calcium-exporting ATPase, Pmc1 of 1096 aas (Furune et al. 2008)..

Eukaryota
Fungi
Pmc1 of Schizosaccharomyces pombe
*3.A.3.2.36









SERCA Ca2+-ATPase of 1093 aas (Docampo et al. 2013).

Eukaryota
Apicomplexa
SERCA ATPase of Toxoplasma gondii
*3.A.3.2.37









SERCA P-type ATPase of 1036 aas.

Eukaryota
Intramacronucleata
SERCA ATPase of Paramecium tetraurelia
*3.A.3.2.38









Plasma membrane Ca2+ ATPase (PMCA) of 1146 aas (Plattner 2014).

Eukaryota
Intramacronucleata
PMCA of Paramecium tetraurelia
*3.A.3.2.39









Plasma membrae Ca2+ ATPase (PMCA) of 1064 aas (Lescasse et al. 2005).

Eukaryota
Intramacronucleata
PMCA of Oxytricha trifallax (Sterkiella histriomuscorum)
*3.A.3.2.40









Plasma membrane Ca2+ ATPase, isoform 2, of 1243 aas, ATP2b2.  The mouse orthologue, of 1198 aas (P9R0I7), when mutated (I1023S in TMS 10 and R561S in the catailytic core) gives rise to semi-dominant hearing loss (Carpinelli et al. 2013).

Eukaryota
Metazoa
ATP2b2 of Homo sapiens
*3.A.3.2.41









P-type Na+-ATPase of 889 aas (Takemura et al. 2009).
Bacteria
Firmicutes
Na+-ATPase of Exiguobacterium aurantiacum
*3.A.3.2.42









Plasma membrane Ca2+-ATPase of 1033 aas, ACA12.  Can replace ACA9 which is normally required for male fertility.  ACA12 is not stimulated by calmodulin (Limonta et al. 2014).

Eukaryota
Viridiplantae
ACA12 of Arabidopsis thaliana
*3.A.3.2.43









SERCA of 1001 aas.  Several 3-D structures are known (e.g., 3W5B).  Molecular dynamics simulations provided evidence for the role of the Mg2+ and K+ bound states in the transport mechanism (Espinoza-Fonseca et al. 2014).  Animal SERCAs are inhibited by three short single TMS membrane proteins, phospholamban (TC# 1.A.50.1), sarcolipin (1.A.50.2) and myoregulin (1.A.50.3), and the inhibitory actions of these peptides on SERCA are counteracted by a peptide called DWORF (Dwarf ORF) (Nelson et al. 2016; Anderson et al. 2015).  Norimatsu et al. 2017 have resolved the first layer of phospholipids surrounding the transmembrane helices. Phospholipids follow the movements of associated residues, causing local distortions and changes in thickness of the bilayer. The entire protein tilts during the reaction cycle, governed primarily by a belt of Trp residues, to minimize energy costs accompanying the large perpendicular movements of the transmembrane helices. A class of Arg residues extend their side chains through the cytoplasm to exploit phospholipids as anchors for conformational switching (Norimatsu et al. 2017).

Eukaryota
Metazoa
SERCA of Oryctolagus cuniculus (rabbit)
*3.A.3.2.44









Crayfish basolateral plasma membrane Ca2+-ATPase, PMCA, of 1190 aas (Wheatly et al. 2007). 80% identical to the human orthologue.

Eukaryota
Metazoa
PMCA of Procambarus clarkii (Red swamp crayfish)
*3.A.3.2.45









The calmodulin-sensitive plasma membrane Ca2+-ATPase (PMCA) of 1080 aas and 10 TMSs.  It has a non-canonical calmodulin (CaM) binding domain that contains a C-terminal 1-18 motif (Pérez-Gordones et al. 2017).

Eukaryota
Kinetoplastida
PMCA of Trypanosoma equiperdum
*3.A.3.2.46









Ca2+-ATPase of 880 aas and 10 TMSs, Ca1.  Key intermediates have been identified; Ca2+ efflux is rate-limited by phosphoenzyme formation. The transport process involves reversible steps and an irreversible step that follows release of ADP and extracellular release of Ca2+ (Dyla et al. 2017).

Bacteria
Firmicutes
Ca1 of Listeria monocytogenes
*3.A.3.2.47









Putative Ca2+ P-type ATPase, TMEM94, of 1356 aas and 10 TMSs in the usual 2 + 2 + 6 TMS arrangement.  This protein is very distantly related to all other members of the 3.A.3.2 family within the P-type ATPase superfamily, and therefore may have a different or unique function (Zhang et al. 2018).

Eukaryota
Metazoa
TMEM94 of Homo sapiens
*3.A.3.2.48









Sarco/endoplasmic reticulum Ca2+ ATPase of 1018 aas and 10 TMSs (Roegner et al. 2018).

Eukaryota
Metazoa
SARCA of Callinectes sapidus
*3.A.3.3.1









H+-ATPase (efflux)
Eukaryota
Fungi
H+-ATPase, plasma membrane of Neurospora crassa
*3.A.3.3.2









H+ (in)/K+ (out) Mg2+-ATPase (antiporter)
Eukaryota
Kinetoplastida
H+/K+ antiport ATPase 1A of Leishmania donovani
*3.A.3.3.3









Mn2+/Cd2+-ATPase, MntA (Hao et al. 1999).
Bacteria
Firmicutes
MntA of Lactobacillus plantarum
*3.A.3.3.4









Putative H+-ATPase
Archaea
Euryarchaeota
Aha1 (MJ1226) of Methanococcus jannaschii
*3.A.3.3.5









Plasma membrane H+-ATPase, TbHA1 (912 aas) (3 isoforms are present in T. brucei) (Luo et al., 2006). This and another H+-ATPase, (UniProt acc # Q388Z3; 97% identical to TbHA1) have been found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

Eukaryota
Kinetoplastida
TbHA1 of Trypanosoma brucei (AAP30857)
*3.A.3.3.6









Plamsa membrane H+-ATPase, Pma1 (pumps protons out of the cell to generate a membrane potential and regulate cytosolic pH) (Liu et al., 2006; Petrov, 2009). TMSs 4,5,6 and 8 comprise the H+ pathway where essential and important residues have been identified (Miranda et al., 2010). Residues in the loop between TMSs 5 and 6 play roles in protein stability, function, and insertion (Petrov 2015).  Pma1 interacts with the plamsa membrane Cch1/Mid1 (1.A.1.11.10) to regulate its activity by influencing the membrane potential (Cho et al. 2016).  Asp739 and Arg811 are important residues for the biogenesis and function of the enzyme as H+ transport determinants (Petrov 2017).

Eukaryota
Fungi
H+-ATPase of Saccharomyces cerevisiae (P05030)
*3.A.3.3.7









Plasma membrane H+ ATPase, AHA1 Three isoforms, AHA1, 2 & 3, exhibit different kinetic properties (Palmgren and Christensen, 1994). Both the N- and C-termini are directly involved in controlling the pump activity (Ekberg et al., 2010). Methyl jasmonate elicits stomatal closure in many plant species including A. thaliana, and stomatal closure is accompanied by large ion fluxes across the plasma membrane.  These events appear to be mediated by AHA1 (Yan et al. 2015).

Eukaryota
Viridiplantae
AHA1 of Arabidopsis thaliana
(P20649)
*3.A.3.3.8









Plasma membrane H+ ATPase, AHA6 (binds 14-3-3 proteins induced by phosphorylation of Thr948, causing activation; preferentially expressed in pollen; Bock et al., 2006) (82% identical to 3.A.3.3.7).

Eukaryota
Viridiplantae
AHA6 of Arabidopsis thaliana (Q9SH76)
*3.A.3.3.9









Proton pumping ATPase, AHA2.  94% identical to AHA1 (3.A.3.3.7); generates the plasma membrane pmf.  Cation-binding pockets have been identified (Ekberg et al. 2010).  The pump has been reconstituted into "nanodiscs" in a functionally monomeric form (Justesen et al. 2013).  Regulated at the post-translation level by cis-acting auto-inhibitory domains, which can be relieved by protein kinase-mediated phosphorylation or binding of specific lipid species such as lysophospholipids (Wielandt et al. 2015).  Pumping is stochastically interrupted by long-lived (~100 seconds) inactive or leaky states. Allosteric regulation by pH gradients modulates the switch between these states but not the pumping or leakage rates (Veshaguri et al. 2016).  They dynamics of the pump have been examined (Guerra and Bondar 2015). AHA2 drives root cell expansion (Hoffmann et al. 2018).

Eukaryota
Viridiplantae
Proton pumping ATPase of Arabidopsis thaliana
*3.A.3.3.10









Plamsa membrane proton-pumping ATPase, Pma1, of 1003 aas and 10 putative TMSs in a 2 + 2 + 6 TMS arrangement.  Leptosphaeria maculans, lacking this enzyme, displays a total loss of pathogenicity towards its host plant (Brassica napus). The mutant is unable to germinate on the host leaf surface and is thus blocked at the pre-penetration stage. Reduction in Pma1 activity may disturb the electrochemical transmembrane gradient, thus leading to conidia defective in turgor pressure generation on the leaf surface. L. maculans possesses a second plasma membrane H+-ATPase-encoding gene, termed pma2 (Remy et al. 2008).

 

Eukaryota
Fungi
Pma1 of Leptosphaeria maculans
*3.A.3.3.11









Probable H+ pumping P-type ATPase of 1068 aas and 10 TMSs, PMA1 (Shan et al. 2006). PnPMA1 is differentially expressed during pathogen asexual development with a more than 10-fold increase in expression in germinated cysts, the stage at which plant infection is initiated, compared to vegetative or sporulating hyphae or motile zoospores.  PnPMA1 contains all the catalytic domains characteristic of H+-ATPases but also has a distinct domain of approximately 155 amino acids that forms a putative cytoplasmic loop between transmembrane domains 8 and 9 (Shan et al. 2006).

Eukaryota
Oomycetes
PMA1 of Phytophthora nicotianae
*3.A.3.3.12









ATPase-7, AHA7, of 961 aas and 10 TMSs. 73% identical to AHA2 with which it shares function.  AHA7 is autoinhibited by a sequence present in the extracellular loop between transmembrane segments 7 and 8. Autoinhibition of pump activity is regulated by extracellular pH, suggesting negative feedback regulation of AHA7 during establishment of an H+ gradient. Restriction of root hair elongation is dependent on both AHA2 and AHA7, with each having different roles in this process (Hoffmann et al. 2018).

Eukaryota
Viridiplantae
AHA7 of Arabidopsis thaliana (Mouse-ear cress)
*3.A.3.4.1









Mg2+/Ni2+-ATPase (uptake)
Bacteria
Proteobacteria
MgtA of Salmonella typhimurium
*3.A.3.4.2









Putative spirochete Mg2+-ATPase, Lin3 (843 aas)
Bacteria
Spirochaetes
Lin3 of Leptospira interrogans (Q72RN5)
*3.A.3.4.3









Mg2+ ATPase (1182 aas; 18-20 TMSs) with an N-terminal (residues 1-325) transmembrane domain of 8-10 TMSs; homologous to residues 493-791 in O53781 of Mycobacterium tuberculosis (TC# 2.A.1.3.43). Residues 257-318 hit TMSs 7 and 8 in FmtC (MrpF), TC#2.A.1.3.37 with a score of 8 e-4. The last 3 TMSs of the N-terminal fused domain of 3.A.3.4.3 and 3.A.3.4.4 are homologous (e-10) to the last 3 TMSs in 2.A.1.3.43. The N-terminal domain is homologous to the 8TMS domains of 9.B.3 family members.

Bacteria
Proteobacteria
Mg2+-ATPase of Pseudomonas stutzeri (F2N2Z6)
*3.A.3.4.4









Mg2+ P-type ATPase (1195 aas; 18-20 TMSs) with an extra N-terminal 8-10 TMSs (residues 1-330). Similar to 3.A.3.4.3. The last 3 TMSs of the N-terminal fused domain to 3.A.3.4.3 and 3.A.3.4.4 are homologous (e-10) to the last 3 TMSs in 9.A.30.2.1. The N-terminal domain is homologous to the 8TMS domains of 9.B.3 family members.

Bacteria
Proteobacteria
Mg2+-ATPase with N-terminal 8-10 TMS domain of ~300 residues of Azotobacter vinelandii (C1DHA2)
*3.A.3.5.1









Cu2+-ATPase (uptake)
Bacteria
Firmicutes
CopA of Enterococcus hirae
*3.A.3.5.2









Cu+-, Ag+-ATPase (efflux)
Bacteria
Firmicutes
CopB of Enterococcus hirae
*3.A.3.5.3









Cu+-, Ag+-ATPase (efflux from the cytosol into the secretory pathway) (Barnes et al., 2005); ATP7B (Wilson's disease protein, α-chain) (continuously expressed in Purkinje neurons). It delivers Cu+ to the ferroxidase, ceruloplasmin, in liver. May also transport Fe2+ (Takeda et al., 2005). Critical roles for the COOH terminus of ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking have been reported (Braiterman et al. 2011).  Modeling suggests that Cu+-binding sites HMBDs 5 and 6 are most important for function (Gourdon et al. 2012).  ATP7B loads Cu+ into newly synthesized cupro-enzymes in the trans-Golgi network and exports excess copper out of cells by trafficking from the Golgi to the plasma membrane.  Mutations causing disease can affect activity, stability or trafficking (Braiterman et al. 2014).  Cisplatin is a poor substrate relative to Cu+with a Km of 1 mμM, and copper and cisplatin compete with each other (Safaei et al. 2008).

Eukaryota
Metazoa
Cu+-ATPase, ATP7B, of Homo sapiens
*3.A.3.5.4









Ag+-ATPase (efflux)
Bacteria
Proteobacteria
Ag+-ATPase, SilP of Salmonella typhimurium
*3.A.3.5.5









Cu+, Ag+-ATPase (efflux) (Fan and Rosen, 2002).  There are two metal binding domains (MBDs). The distal N-terminal MBD1 possesses a function analogous to the metallochaperones of related prokaryotic copper resistance systems and is involved in copper transfer to the membrane-integral ion binding sites of CopA. In contrast, the proximal domain MBD2 has a regulatory role by suppressing the catalytic activity of CopA in absence of copper (Drees et al. 2015).

 

Bacteria
Proteobacteria
CopA of E. coli
*3.A.3.5.6









Cu+-ATPase, ATP7A (MNK or Mc1) (efflux from the cytosol into the secretory pathway) (Menkes disease protein, α-chain) (Tümer 2013). Expressed in Purkinje cells early in development and later in Bergmann glia. In melanocytes, it delivers Cu2+ to tyrosinase (Barnes et al., 2005). ATP7A has dual functions: 1) it incorporates copper into copper-dependent enzymes; and 2) it maintains intracellular copper levels by removing excess copper from the cytosol. To accomplish both functions, the protein traffics between different cellular locations, depending on copper levels (Bertini and Rosato, 2008). The lumenal loop Met672-Pro707 of copper-transporting ATPase ATP7A binds metals and facilitates copper release from the intramembrane sites (Barry et al., 2011).  Modeling suggests that Cu+-binding sites HMBDs 5 and 6 are most important for function (Gourdon et al. 2012).  In addition to X-linked recessive Menkes disease, mutations cause occipital horn syndrome and adult-onset distal motor neuropathy (Yi and Kaler 2014). p97/VCP interacts with ATP7A playing a role in motor neuron degeneration (Yi and Kaler 2018).

Eukaryota
Metazoa
ATP7A of Homo sapiens
*3.A.3.5.7









Cu+-Ag+-ATPase (efflux), CopA of 804 aas. Exhibits maximal activity at 75˚C (Cattoni et al., 2007). The 3-D structure of the ATP-binding domain has been solved (2HC8_A) (functions with the Cu+ chaperone, CopZ; 130aas) (González-Guerrero and Argüello, 2008). This protein has both N- and C- terminal metal binding domains (MBDs). The N-MBD exhibits a conserved ferredoxin-like fold, binds metals to CXXC, and regulates turnover. The C-MBD interacts with the ATP-binding (ATPB) domain and the actuator (A) domain (Agarwal et al., 2010). Cysteine is a non-essential activator of CopA, interacting with the cytoplasmic side of the enzyme in the E1 form (Yang et al. 2007).

Archaea
Euryarchaeota
CopAZ of Archaeoglobus fulgidus:
CopA (PaeS) (O29777)
CopZ (2HU9_A; O29901)
*3.A.3.5.8









Cu+ transporting ATPase (intracellular, in the trans-Golgi membrane), Ccc2

Eukaryota
Fungi
Ccc2 of Candida albicans
*3.A.3.5.9









Cu+ transporting (copper detoxification) ATPase, Crp1
Eukaryota
Fungi
Crp1 of Candida albicans
*3.A.3.5.10









Cu+ (Km 0.3 μM), Ag+ transporting ATPase, CopB (Mana-Capelli et al., 2003)

Archaea
Euryarchaeota
CopB of Archaeoglobus fulgidus (AAB91079)
*3.A.3.5.11









Chloroplast envelope Cu+-uptake ATPase, PAA1 or HMA1.  Essential for growth under adverse light conditions (Seigneurin-Berny et al. 2006).

Eukaryota
Viridiplantae
PAA1 of Arabidopsis thaliana (Q9SZC9)
*3.A.3.5.12









Chloroplast thylakoid Cu+-ATPase, PAA2/HMA8 (delivers Cu+ to the thylakoid lumen).  Degraded by the Clp protease undeer conditions of Cu+ excess (Tapken et al. 2014).

Eukaryota
Viridiplantae
PAA2 of Arabidopsis thaliana (AAP55720)
*3.A.3.5.13









The archaeal Cu+ efflux pump (CopA)

Archaea
Crenarchaeota
CopA of Sulfolobus solfataricus (Q97UU7)
*3.A.3.5.14









The yeast Cd2+ efflux pump, PCA1 (Adle et al., 2007)
Eukaryota
Fungi
PCA1 of Saccharomyces cerevisiae (P38360)
*3.A.3.5.15









The transferable, plasmid-localized, copper sensitivity (uptake) ATPase, TcrA (811aas) (46% identical to 3.A.3.5.1) (Hasman, 2005)

Bacteria
Firmicutes
TcrA of Enterococcus faecium (ABA39707)
*3.A.3.5.16









The transferable, plasmid-localized, copper resistance (efflux) ATPase, TcrB (50% identical to 3.A.3.5.2) (Hasman, 2005)

Bacteria
Firmicutes
TcrB of Enterococcus faecium (AAL05407)
*3.A.3.5.17









Golgi Cu2+ ATPase, Ccc2, retrieves Cu2+ from the metallochaperone Atx1 and transports it to the lumen of Golgi vesicles (Lowe et al., 2004)

Eukaryota
Fungi
Ccc2 of Saccharomyces cerevisiae
(P38995)
*3.A.3.5.18









The copper resistance ATPase, CopA (Ettema et al., 2006Lübben et al., 2007; Villafane et al., 2009).

Bacteria
Firmicutes
CopA of Bacillus subtilis (O32220)
*3.A.3.5.19









The Cu2+, Fe3+, Pb2+ resistance efflux pump, CopA (induced by copper and to a lesser extent by Fe3+ and Pb2+) (Sitthisak et al., 2007)
Bacteria
Firmicutes
CopA of Staphylococcus aureus (Q7A3E6)
*3.A.3.5.20









The gold (Au2+) resistance ATPase, GolT (regulated by GolS in response to Au2+; it may function with a cytoplasmic metal binding protein, GolB (AAL19308; Pontel et al., 2007).
Bacteria
Proteobacteria
GolT of Salmonella enterica (Q8ZRG7)
*3.A.3.5.21









The Cu+, Ag+-ATPase, CtrA2 (Chintalapati et al., 2008)
Bacteria
Aquificae
CtrA2 of Aquifex aeolicus (O67432)
*3.A.3.5.22









The Cu2+-ATPase, CtrA3 (Chintalapati et al., 2008)
Bacteria
Aquificae
CtrA3 of Aquifex aeolicus (O67203)
*3.A.3.5.23









Putative spirochete Cu+ ATPase (6 proteins in spirochetes)
Bacteria
Spirochaetes
Lin1 of Leptospira interrogans (Q72N56)
*3.A.3.5.24









The putative copper ATPase, Sso1 (PacS)
Archaea
Crenarchaeota
PacS of Sulfolobus solfataricus (Q97VH4)
*3.A.3.5.25









The putative copper ATPase, Pae1
Archaea
Crenarchaeota
Pae1 of Pyrobaculum aerophilum (Q8ZUJ0)
*3.A.3.5.26









The putative copper ATPase, Tro1
Archaea
Euryarchaeota
Tro1 of Thermoplasma volcanium (Q978Z8)
*3.A.3.5.27









Putative Copper P-type ATPase (46% identical to 3.A.3.5.10)

Archaea
Korarchaeota
Putative Copper P-type ATPase of Candidatus Korarchaeum cryptofilum (B1L487)
*3.A.3.5.28









The putative copper ATPase, Ape2
Archaea
Crenarchaeota
Ape2 of Aeropyrum pernix (Q9YBZ6)
*3.A.3.5.29









The copper (Cu2+) transporting ATPase, Ccc2

Eukaryota
Fungi
Ccc2 of Schizosaccharomyces pombe (O59666)
*3.A.3.5.30









Copper (Cu+) exporting P-ATPase, CopA (3-D structure known to 3.2 Å; PDB# 3RFU; Gourdon et al. 2011).  The internal surface of the ATPase interacts with the copper chaparone, CopZ (Padilla-Benavides et al. 2012).  A sulfur-lined metal transport pathway has been identified (Mattle et al. 2015).  Cu+ is bound at a high-affinity transmembrane-binding site in trigonal-planar coordination with the Cys residues of the conserved CPC motif of transmembrane segment 4 (C382 and C384) and the conserved Methionine residue of transmembrane segment 6 (M717 of the MXXXS motif). These residues are also essential for transport (Mattle et al. 2015).

Bacteria
Proteobacteria
CopA of Legionella pneumophila (Q5X2N1)
*3.A.3.5.31









Mycobacterial copper transporter, MctB (Wolschendorf et al., 2011).

Bacteria
Actinobacteria
MctB of Mycobacterium abscessus (B1MHH7)
*3.A.3.5.32









Copper-transporting ATPase RAN1 (EC 3.6.3.4) (Protein HEAVY METAL ATPASE 7) (Protein RESPONSIVE TO ANTAGONIST 1)
Eukaryota
Viridiplantae
RAN1 of Arabidopsis thaliana
*3.A.3.5.33









Ca2+ exporting ATPase, CopA. The domain organization and mechanism have been studied (Hatori et al., 2009, Hatori et al., 2008, Hatori et al., 2007).  Residues involved in catalysis have been defined (Hatori et al. 2009).

Bacteria
Thermotogae
CopA of Thermotoga martima (Q9WYF3)
*3.A.3.5.34









Cu+ export ATPase, CopA1, required to maintain cytoplasmic copper levels (González-Guerrero et al. 2010; Raimunda et al. 2013).

Bacteria
Proteobacteria
CopA1 of Pseudomonas aeruginosa
*3.A.3.5.35









Functionally uncharacterized P-type ATPase.  Three proteins from Corynebacteria of 841-976 aas are similar in sequence.  Formerly members of the FUPA26 family (Chan et al. 2010).

Bacteria
Actinobacteria
Uncharacterized ATPase of Corynebacterium diphtheriae (Q6NJJ6)
*3.A.3.5.36









Functionally uncharacterized P-type ATPase, formerly of family 28 (FUPA28).  Two proteins in γ-proteobacteria are similar in sequence; of 847-852 aas (Chan et al. 2010).

Bacteria
Proteobacteria
P-type ATPase (formerly FUPA28a) of Legionella pneumophila (Q5ZYY0)
*3.A.3.5.37









Copper exporting ATPase, ATP7 of 1254 aas and 10 - 12 TMSs.  DmATP7 is the sole Drosophila melanogaster ortholog of the human MNK and WND copper transporters. A regulatory element drives expression in all neuronal tissues examined and demonstrates copper-inducible, Mtf-1-dependent expression in the larval midgut. Thus, an important functional role for copper transport in neuronal tissues is implied. Regulation of DmATP7 expression is not used to limit copper absorption under toxic copper conditions. The protein localizes to the basolateral membrane of DmATP7 expressing midgut cells, supporting a role in export of copper from midgut cells (Burke et al. 2008).

Eukaryota
Metazoa
ATP7 of Drosophila melanogaster (Fruit fly)
*3.A.3.5.38









Cuprous ion (Cu+) exporter, CopB, of 785 aas and 8 TMSs in a 4 + 2 + 2 arrangement. The copper-transporting P1B-ATPases have been divided traditionally into two subfamilies, the P1B-1-ATPases or CopAs and the P1B-3-ATPases or CopBs. CopAs selectively export Cu+ whereas previous studies have suggested that CopBs are specific for Cu2+ export. Biochemical and spectroscopic characterization of Sphaerobacter thermophilus CopB (StCopB) showed that, while it does bind Cu2+, the binding site is not in the transmembrane domain (Purohit et al. 2018).  StCopB exhibits metal-stimulated ATPase activity in response to Cu+, but not Cu2+, indicating that it is actually a Cu+ transporter. Cu+ is coordinated by four sulfur ligands derived from conserved cysteine and methionine residues. The histidine-rich N-terminal region is required for maximal activity, but is inhibitory in the presence of divalent metal ions. P1B-1- and P1B-3-ATPases may therefore all transport Cu+ (Purohit et al. 2018).

Bacteria
Chloroflexi
CopB of Sphaerobacter thermophilus
*3.A.3.5.39









Cu+, Zn2+, Cd2+ exporting ATPase of 815 aas and 8 TMSs, CueA. Has two N-terminal metal binding domains that are essential for resistance to these three metal ions (Liang et al. 2016).

Bacteria
Proteobacteria
CueA of Bradyrhizobium liaoningense
*3.A.3.6.1









Zn2+-, Cd2+-, Pb2+-ATPase (efflux).  The enzyme from S. aureus strain 17810R, of 726 aas, functions as a Cd2+:H+ antiporter, using both the pmf and ATP hydrolysis to drive Cd2+ expulsion (Tynecka et al. 2016).

Bacteria
Firmicutes
CadA of Staphylococcus aureus
*3.A.3.6.2









Zn2+-, Cd2+-, Co2+-, Hg2+-, Ni2+-, Cu2+, Pb2+-ATPase (efflux) (Hou and Mitra, 2003)
Bacteria
Proteobacteria
ZntA of E. coli
*3.A.3.6.3









Cd2+-, Zn2+, Co2+-ATPase (efflux)
Bacteria
Proteobacteria
CadA (HP0791) of Helicobacter pylori
*3.A.3.6.4









Pb2+-ATPase (efflux), PbrA.  Mediates resistance to Pb2+, Cd2+ and Zn2+.  Lead resistance is facilitated by the phosphatase, PbrB, possibly by allowing complexation of the Pb2+ by phosphate in the periplasm (Hynninen et al. 2009).

 

Bacteria
Proteobacteria
PbrA of Ralstonia metallidurans
*3.A.3.6.5









Mono- and divalent heavy metal (Cu+, Ag+, Zn2+, Cd2+) ATPase, Bxa1. bxa1 gene expression is induced by all four heavy metal ions (Tong et al., 2002). The His-rich domain is essential for both monovalent (Ag+ and Cu+) and divalent ( Cd2+ and Zn2+) metal tolerance (Nakakihara et al. 2009).

Bacteria
Cyanobacteria
Bxa1 ATPase of Oscillatoria brevis
*3.A.3.6.6









Chloroplast envelope Cu+-ATPase, HMA1 (Seigneurin-Berny et al., 2006). Transports many heavy metals (Zn2+, Cu2+, Cd2+, Co2+), increasing heavy metal tolerance. Also transports Ca2+ (Km=370nM) in a thapsigargin-sensitive fashion (Moreno et al, 2008).
Eukaryota
Viridiplantae
HMA1 of Arabidopsis thaliana
(Q9M3H5)
*3.A.3.6.7









The Zn2+ (and Cd2+)-ATPase, HMA2. HMA2 maintains metal homeostasis and has a long C-terminal sequence rich in Cys and His residues that binds Zn2+, Kd≈16 nM and regulates activity (Eren et al., 2006).
Eukaryota
Viridiplantae
HMA2 of Arabidopsis thaliana (Q9SZW4)
*3.A.3.6.8









The Cd2+ resistance ATPase, CadA (Wu et al., 2006)

Bacteria
Firmicutes
CadA of Listeria monocytogenes (Q60048)
*3.A.3.6.9









The Zn2+ uptake ATPase, ZosA (YkvW) (Gaballa and Helmann, 2002)
Bacteria
Firmicutes
ZosA of Bacillus subtilis (O31688)
*3.A.3.6.10









The Cd2+, Zn2+, Co2+ resistance ATPase, CadA (YvgW)
Bacteria
Firmicutes
CadA of Bacillus subtilis (O32219)
*3.A.3.6.11









The Zn2+ efflux P-type ATPase, CadA1 (Leedjarv et al., 2007)
Bacteria
Proteobacteria
CadA1 of Pseudomonas putida (Q88RT8)
*3.A.3.6.12









The Cd2+/Pb2+ resistance P-type ATPase, CadA2; induced by Zn2+, Cd2+, Pb2+, Ni2+, Co2+ and Hg2+ (Leedjarv et al., 2007)
Bacteria
Proteobacteria
CadA2 of Pseudomonas putida (Q88CP1)
*3.A.3.6.13









The heavy metal efflux pump, AztA (exports Zn2+, Cd2+, Pb2+; has two adjacent heavy metal binding domains (Liu et al., 2007)

Bacteria
Cyanobacteria
AztA of Anabaena (Nostoc) sp. PCC7120 (Q8ZS90)
*3.A.3.6.14









The heavy metal (Zn2+, Cd2+) P-type ATPase, Smc04128 (Rossbach et al., 2008)
Bacteria
Proteobacteria
Smc04128 of Sinorhizobium meliloti (Q92T56)
*3.A.3.6.15









The heavy metal transporter A (HmtA) mediates uptake of copper and zinc but not of silver, mercury, or cadmium (Lewinson et al., 2009).

Bacteria
Proteobacteria
HmtA of Pseudomonas aeruginosa (Q9I147)
*3.A.3.6.16









The putative heavy metal ATPase, Mac1
Archaea
Euryarchaeota
Mac1 of Methanosarcina acetivorans (Q8TJZ4)
*3.A.3.6.17









Cd2+-selective export ATPase, HMA3 (expressed in root cell tonoplasts wherein Cd2+ is sequestered (Ueno et al., 2010)).

Eukaryota
Viridiplantae
HMA3 of Oryza sativa (Q8H384)
*3.A.3.6.18









Cd2+/Zn2+ exporting ATPase, HMA4. (very similar to HMA3; TC# 3.A.3.6.7). Important for Zn2+ nutrition. Has a C-terminal domain containing 13 cysteine pairs and a terminal stretch of 11 histidines with a high affinity for Zn2+ and Cd2+ and a capacity to bind 10 Zn2+ ions per C-terminus (Baekgaard et al., 2010).

Eukaryota
Viridiplantae
HMA4 of Arabidopsis thaliana (O64474)
*3.A.3.6.19









Ca2+/Zn2+ ATPase, OsHMA2 (Satoh-Nagasawa et al., 2012).

Eukaryota
Viridiplantae
HMA2 of Oryza sativa (E7EC32)
*3.A.3.6.20









Cadmium/zinc-transporting ATPase 4, HMA3

Eukaryota
Viridiplantae
HMA3 of Arabidopsis thaliana
*3.A.3.6.21









Cobalt ion exporting ATPase, slr0797 (Rutherford et al. 1999).

Bacteria
Cyanobacteria
Co-ATPase of Synechocystis PCC6803
*3.A.3.6.22









Co2+-specific P1B-ATPase, CoaT (Zielazinski et al., 2012).

Bacteria
Proteobacteria
CoaT of Sulfitobacter sp. NAS-14.1 (A3T2G5)
*3.A.3.6.23









Heavy metal (Pb2+, Cd2+, Zn2+) export ATPase of 970 aas, PbtA (Hložková et al. 2013; Suman et al. 2014)

Bacteria
Proteobacteria
PbtA of Achromobacter xylosoxidans
*3.A.3.6.24









Fur-regulated virulence factor A of 626 aas, FrvA; suggested by the authors to be a heme exporter, but maybe more likely to be an iron exporter (McLaughlin et al. 2012).

Bacteria
Firmicutes
FrvA of Listeria monocytogenes
*3.A.3.6.25









Cd2+/Zn2+/Co2+ export ATPase, ZntA, of 904 aas and 8 TMSs. Expression of the zntA gene is inducible by all three metal ions, with Cd2+ being the most potent, mediated by the MerR-like regulator, ZntR (Chaoprasid et al. 2015). zntA and zntR mutants were highly sensitive to CdCl2 and ZnCl2, and less sensitive to CoCl2. Inactivation of zntA increased the accumulation of intracellular cadmium and zinc and conferred hyper-resistance to H2O2. Thus, ZntA and its regulator, ZntR, are important for controlling zinc homeostasis and cadmium and cobalt detoxification. The loss of either the zntA or zntR gene did not affect the virulence of A. tumefaciens in Nicotiana benthamiana (Chaoprasid et al. 2015).

Bacteria
Proteobacteria
ZntA of Agrobacterium tumefaciens
*3.A.3.6.26









Cadmium/zinc resistance efflux pump, CadA of 910 aas and 8 TMSs (Maynaud et al. 2014).

Bacteria
Proteobacteria
CadA of Mesorhizobium metallidurans
*3.A.3.6.27









Transition metal efflux ATPase of 829 aas and 6 TMSs, CzcP.  Exports Zn2+, Cd2+ and Co2+ efficiently (Scherer and Nies 2009). The side chains of Met254, Cys476, and His807 contribute to Cd2+, Co2+, and Zn2+ binding and transport (Smith et al. 2017).

Bacteria
Proteobacteria
CzcP of Cupriavidus metallidurans (Ralstonia metallidurans)
*3.A.3.7.1









K+-ATPase (uptake), KdpFABC. (KdpA is homologous to other K+ transporters such as KcsA (1.A.1.1.1), KtrB (2.A.38.4.2 and 2.A.38.4.3), and HKT (2.A.38.3.1 and 2.A.38.3.2); KdpB is homologous to P-ATPase α-subunits; KdpC and KdpF may facilitate complex assembly and stabilize the complex (Bramkamp et al., 2007; Haupt et al., 2005; Greie and Altendorf, 2007; Irzik et al., 2011). The KdpFABC acts as a functional and structural dimer with the two KdpB subunits in direct contact, but the enzyme can dissociate to the monomer (Heitkamp et al., 2008). KdpF is part of and stabilizes the KdpABC complex (Gassel et al., 1999).  Transcription of the kdp operon is activated by the KdpDE sensor kinase/response regulator pair, and unphosphorylated IIANtr of the PTS (TC# 4.A) binds KdpD to stimulate its activity, thereby enhancing kdp operon expression (Lüttmann et al. 2009, Lüttmann et al. 2015). Transcriptional regulation of the Pseudomonas putida kdpFABC operon by the KdpDE sensor kinase/response regulator by direct interaction of IIANtr of the PTS with KdpD has also been studied (Wolf et al. 2015).
The 2.9 Å X-ray structure of the complete Escherichia coli KdpFABC complex with a potassium ion within the selectivity filter of KdpA and a water molecule at a canonical cation site in the transmembrane domain of KdpB has been solved (Huang et al. 2017). The structure reveals two structural elements that appear to mediate the coupling between these two subunits: a protein-embedded tunnel runs between these potassium and water sites, and a helix controlling the cytoplasmic gate of KdpA is linked to the phosphorylation domain of KdpB. A mechanism that repurposes protein channel architecture for active transport across biomembranes was proposed (Huang et al. 2017).

Bacteria
Proteobacteria
KdpABCF of E. coli
KdpA (P03959)
KdpB (P03960)
KdpC (P03961)
KdpF (P36937)
*3.A.3.7.2









High affinity potassium uptake ATPase, KdpABC.  Regulated by direct interaction of the IIANtr protein with the sensor kinase/response regulator, KdpDE (Prell et al. 2012).

Bacteria
Proteobacteria
KdpABC of Rhizobium leguminosarum
*3.A.3.8.1









Golgi Aminophospholipid (phosphatidyl serine and phosphatidyl ethanolamine) translocase (flipping from the exofacial to the cytosolic leaflet of membranes to generate phospholipid asymmetry), required for vesicle-mediated protein transport from the Golgi and endosomes. The system has been reconstituted after purification in proteoliposomes. It flips phosphatidyl serine but not phosphatidylcholine or sphinogomyelin (Zhou and Graham, 2009).  A unified mechanism of flipping for ABC and P-type ATPases has been proposed (López-Marqués et al. 2014).

Eukaryota
Metazoa
ATPase II of Bos taurus
*3.A.3.8.2









Golgi aminophospholipid translocase (flipping from the exofacial to the cytosolic leaflet of membranes), required for vesicle-mediated protein transport from the Golgi and endosomes (Pomorski et al., 2003). The system has been reconstituted after purification in proteoliposomes. It flips phosphatidyl serine but not phosphatidylcholine or sphingomyelin (Zhou and Graham, 2009).  Drs2p (ACT3; ATP8A2), required for phospholipid translocation across the Golgi membrane: PL (in) ATP → PL (out) ADP Pì (flippase activity). Interacts with CDC50 (Bryde et al., 2010). Activated by ArfGEF when bound to the C-terminus (Natarajan et al. 2009). The beta-subunit, CDC50A, allows the stable expression, assembly, subcellular localization, and lipid transport activity of the P4-ATPase ATP8A2 (Coleman and Molday, 2011).

Eukaryota
Fungi
DRS2 of Saccharomyces cerevisiae
*3.A.3.8.3









Miltefosine/glycerophospholipid uptake translocase and phospholipid uptake flippase, MIL (Pérez-Victoria et al., 2003)

Eukaryota
Kinetoplastida
MIL of Leishmania donovani (Q6VXY9)
*3.A.3.8.4









Inwardly directed phospholipid and lysophospholipid (phosphatidylcholine, phosphatidyl serine and lysophosphoethanolamine) flippase, Dnf1 (functions with the β-subunit, Lem3) (Elvington et al., 2005; Pomorski et al., 2003; Riekhof and Voelker, 2006; Riekhof et al., 2007) Also transports the anti-neoplastic and anti-parasitic ether lipid substrates related to edelfosine (Riekhof and Voelker, 2009) (is not required for phosphotidyl serine inwardly directed flipping (Stevens et al. 2008)). Transports diacyl phospholipids in preference to lyso (monoacyl) phospholipids (Baldridge et al. 2013).  A conserved asparagine (N220) in the first transmembrane segment specifies glycerophospholipid binding and transport, but specific substitutions at this site allow transport of sphingomyelin (Roland and Graham 2016).

Eukaryota
Fungi
Dnf1 of Saccharomyces cerevisiae (P32660)
*3.A.3.8.5









Inwardly directed phosphatidylcholine, phosphatidyl serine, and lysophosphoethanolamine flippase, Dnf2 (functions with the β-subunit, Lem3) (Elvington et al., 2005; Pomorski et al., 2003; Riekhof and Voelker, 2006; Riekhof et al., 2007). This plasma membrane P-type ATPase (ACT4) is a phospholipid flippase that contributes to endocytosis, protein transport and all polarity (Hua et al., 2002). Transports monoacyl (lyso) phospholipids much better than diacyl phospholipids, but can be mutated to transport diacyl phospholipids (Baldridge et al. 2013).

Eukaryota
Fungi
Dnf2 of Saccharomyces cerevisiae (Q12675)
*3.A.3.8.6









Golgi phospholipid transporting (flipping) ATPase3 (1213aas; 10TMSs). Involved in growth of roots and shoots. Uses a β-ATPase3 subunit, ALIS1 (TC#8.A.27.4) (Paulsen et al., 2008).
Eukaryota
Viridiplantae
ATPase3/ALIS1 of Arabidopsis thaliana (Q9XIE6)
*3.A.3.8.7









The aminophospholipid ATPase1 (ALA1) (mediate chilling tolerance; Gomes et al., 2000).  Promotes antiviral silencing (Guo et al. 2017).

Eukaryota
Viridiplantae
ALA1 of Arabidopsis thaliana (P98204)
*3.A.3.8.8









The phosphatidylserine flippase in photoreceptor disc membranes, ATP8A2 (Coleman et al., 2009). The beta-subunit, CDC50A, allows the stable expression, assembly, subcellular localization, and lipid transport activity of ATP8A2 (Coleman and Molday, 2011).  Missennse mutations in ATP8A2 are associated with cerebellar atrophy and guadrupedal locomotion (Emre Onat et al. 2012).

Eukaryota
Metazoa
ATP8A2 of Mus musculus (P98200)
*3.A.3.8.9









The phospholipid flipping ATPase (contributes to vesicle biogenesis in the secretory and endocytic pathways). Forms heteromeric complexes with ALIS Cdc50-like β-subunits (ALIS1 = Q9LTW0; TC#8.A.27.1.4) promoting functionality (López-Marqués et al., 2010). The beta-subunit, CDC50A, allows the stable expression, assembly, subcellular localization, and lipid transport activity of the P4-ATPase ATP8A2 (Coleman and Molday, 2011). Promotes antiviral silencing (Guo et al. 2017).

Eukaryota
Viridiplantae
Ala2 of Arabidopsis thaliana (P98205)
*3.A.3.8.10









Lipid flippase, Apt1 (involved in stress tolerance and virulence). Deletion of Apt1 causes (1) altered actin distribution, (2) increased sensitivity to stress conditions (oxidative and nitrosative stress) and to trafficking inhibitors, such as brefeldin A and monensin, a reduction in exported acid phosphatase activity, and (3) hypersensitivity to the antifungal drugs amphotericin B, fluconazole, and cinnamycin (Hu and Kronstad, 2010).

Eukaryota
Fungi
Apt1 of Cryptococcus neoformans (Q5KP96)
*3.A.3.8.11









Phospholipid (e.g., cardiolipin) transporter, Atp8b1. A mutant version is associated with severe
pneumonia in humans and mice. It binds and internalizes cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessens bacterium-induced lung injury and improves
survival (Ray et al., 2010).  Mutations have been identified that give rise to progressive familial intrahepatic cholestasis (Stone et al. 2012).  This lipid flippase forms a heterodimer with CDC50A/Transmembrane protein 30A (TC# 8.A.27.1.5) and is essential for surface expressioin of the apical Na+-bile acid transporter, Slc10A2/ASBT (TC#2.A.28.1.2) (van der Mark et al. 2014).

Eukaryota
Metazoa
Atp8b1 of Homo sapiens (O43520)
 
*3.A.3.8.12









Probable phospholipid-transporting ATPase IF (EC 3.6.3.1) (ATPase IR) (ATPase class VI type 11B)
Eukaryota
Metazoa
ATP11B of Homo sapiens
*3.A.3.8.13









Probable phospholipid-transporting ATPase IA (EC 3.6.3.1) (ATPase class I type 8A member 1) (Chromaffin granule ATPase II).  Also found in the liver canicular membrane (Chaubey et al. 2016).

Eukaryota
Metazoa
ATP8A1 of Homo sapiens
*3.A.3.8.14









ATP11C aminophospholipid (phosphatidyl serine and phosphatidyl ethanolamine, but not phosphatidyl choline) flippase.  Dependent on CDC50A for proper localization to the plasma membrane, and possibly also for activity (Segawa et al. 2014).  Present in liver basolateral membranes (Chaubey et al. 2016).

Eukaryota
Metazoa
ATP11C of Homo sapiens
*3.A.3.8.15









Phospholipid transporting ATPase, Tat1 of 1139 aas.  Transports phosphatidylserine from the outer to the inner leaflet of the plasma membrane, thereby maintaining the enrichment of this phospholipid in the inner leaflet. Ectopic exposure of phosphatidylserine on the cell surface may result in removal of living cells by neighboring phagocytes in an apoptotic process (Darland-Ransom et al. 2008).  Tat1 regulates lysosome biogenesis and endocytosis as well as yolk uptake in oocytes. It is required at multiple steps of the endolysosomal pathway, at least in part by ensuring proper trafficking of cell-specific effector proteins (Ruaud et al. 2009).

Eukaryota
Metazoa
Tat1 of Caenorhabditis elegans
*3.A.3.8.16









ATP9A lipid flippase of 1047 aas and 10 TMSs.  Present in the liver canicular membrane (Chaubey et al. 2016).

Eukaryota
Metazoa
ATP9A of Homo sapiens
*3.A.3.8.17









Intracellular phospholipid flippase ATP11A (Chaubey et al. 2016).  Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. May be involved in the uptake of farnesyltransferase inhibitor drugs, such as lonafarnib (Zhang et al. 2005).

Eukaryota
Metazoa
ATP11A of Homo sapiens
*3.A.3.8.18









The essential endosomal Neo1 phospholipid flipping ATPase of 1151 aas.  Neo1 plays an essential role in establishing phosphatidyl serine (PS) and phosphatidyl ethanolamine (PE) plasma membrane asymmetry in budding yeast (Takar et al. 2016).

Eukaryota
Fungi
Neo1 of Saccharomyces cerevisiae
*3.A.3.8.19









The Leishmania miltefosine transporter (LMT) is a plasma membrane P4-ATPase that catalyses translocation into the parasite of the leishmanicidal drug, miltefosine as well as phosphatidylcholine and phosphatidylethanolamine analogues. Five highly-conserved amino acids in the cytosolic N-terminal tail (Asn58, Ile60, Lys64, Tyr65 and Phe70) and two (Pro72 and Phe79) in the first TMS were examined, and several of these were important for activity (Perandrés-López et al. 2018). The beta subunit of this system has TC# 8.A.27.1.3.

Eukaryota
Kinetoplastida
LMT of Leishmania amazonensis
*3.A.3.8.20









Plasma membrane phospholipid flippase of 1656 aas, Dnf3-Crf1. Dnf3 flips phospholipids from the outer leaflet of the membrane to the inner leaflet (Sartorel et al. 2015). Crf1, a non-catalytic subunit, regulates the activity of Dnf3.  It is listed under TC# 8.A.27.1.7.

Eukaryota
Fungi
Dnf3/Crf1 of Saccharomyces cerevisiae
*3.A.3.8.21









Putative lipid flipping ATPase of 922 aas and 10 TMSs (Greiner et al. 2018).

Viruses
Mimiviridae
ATPase of Klosneuvirus KNV1
*3.A.3.8.22









Probable phospholipid-transporting P-type ATPaseof 903 aas and  10 TMSs.

Viruses
Mimiviridae
ATPase of Tupanvirus soda lake
*3.A.3.8.23









Possible lipid flipping P-type ATPase of 809 aas and 7 putative TMSs.  It is probably C-terminally truncated.

Viruses
Mimiviridae
ATPase of Catovirus CTV1
*3.A.3.9.1









Na+-ATPase (efflux)
Eukaryota
Fungi
Pmr2ap (ENa1) of Saccharomyces cerevisiae
*3.A.3.9.2









K+-ATPase (efflux)
Eukaryota
Fungi
Cta3 of Schizosaccharomyces pombe
*3.A.3.9.3









Monovalent alkali cation (Na+ and K+) ATPase (efflux of both cations)
Eukaryota
Fungi
ENA2 of Debaryomyces occidentalis
*3.A.3.9.4









Na+ ATPase, ENA1 (Watanabe et al., 2002)
Eukaryota
Fungi
ENA1 of Zygosaccharomyces rouxii (BAA11411)
*3.A.3.9.5









Plasma membrane K+ or Na+ efflux ATPase (required for growth at pH9, and for Na+ or K+ tolerance above pH8; Benito et al., 2009) (50% identical to 3.A.3.9.3).
Eukaryota
Fungi
Ena1 of Ustilago maydis (B5B9V9)
*3.A.3.9.6









Endoplasmic reticulum K+ or Na+ efflux ATPase; confers Na+ resistance (Benito et al., 2009) (43% identical to 3.A.3.9.2).
Eukaryota
Fungi
Ena2 of Ustilago maydis (Q4PI59)
*3.A.3.9.7









P-type Ca2+ ATPase of 1041 aas and 12 TMSs.  Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

Eukaryota
Kinetoplastida
P-type Ca2+ ATPase of Trypanosoma brucei  
*3.A.3.10.1









P-type ATPase 13a1 of 1193 aas

Eukaryota
Viridiplantae
ATPase 13a1 of Ricinus communis (Castor bean)
*3.A.3.10.2









Zebrafish ATP13A2 (Parkinson''s disease protein) is essential for embryonic survival (Lopes da Fonseca et al. 2013).

Eukaryota
Metazoa
ATP13A2 of Danio rerio (Q7SXR0)
*3.A.3.10.3









The endoplasmic reticular ATPase, Spf1 or Cod1. Plays a role in ER Mn2+ homeostasis by pumping Mn2+ into the ER lumen (Cronin et al., 2002; Cohen et al. 2013). Deletion of the gene results in ER stress and lowered Mn2+ in the ER lumen (Cohen et al. 2013).

Eukaryota
Fungi
Spf1 of Saccharomyces cerevisiae (P39986)
*3.A.3.10.4









P-type ATPase of 1308 aas

Eukaryota
Apicomplexa
ATPase of Babesia equi
*3.A.3.10.5









P-type ATPase of 1291 aas

Eukaryota
Apicomplexa
ATPase of Cryptosporidium parvum
*3.A.3.10.6









Putative Mn2+-exporting P-type ATPase of 1146 aas.

Eukaryota
Fungi
APase of Encephalitozoon cuniculi (Q8SRH4)
*3.A.3.10.7









This protein was orginally designated the functionally uncharacterized P-type ATPase, FUPA13 (Thever and Saier 2009).  It is the Parkinson''s disease (PD) gene product, PARK9, also called ATP13A2, and its defect gives rise to multiple abnormalities (Dehay et al. 2012).  It is similar to the probable manganese exporter in yeast, Ypk1 (TC# 3.A.3.10.8), and may have the same function, but in lysosomes. Toxic levels of manganese cause a syndrome simiilar to PD (Chesi et al. 2012).  Manganese homeostasis in the nervous system has been reviewed (Chen et al. 2015).  The progression of PD may involve the lysosome and different autophagy pathways (Gan-Or et al. 2015).  It also exhibits an activity-independent scaffolding role in trafficking/export of intracellular cargo in response to proteotoxic stress (Demirsoy et al. 2017).

Eukaryota
Metazoa
PARK9 of Homo sapiens
*3.A.3.10.8









This protein was originally designated the functionally uncharacterized P-type ATPase 14 (FUPA14) (Thever and Saier 2009), but it has been shown to be a vacuolar ATPase, Ypk1, that functions in manganese detoxification and homeostasis (Chesi et al. 2012).  It therefore is likely to catalyze export of manganese ions from the cytoplasm into the vacuole.

Eukaryota
Fungi
Ypk1 of Saccharomyces cerevisiae (gi6324865)
*3.A.3.10.9









This protein was previously designated the functionally uncharacterized P-type ATPase (FUPA15) (Thever and Saier 2009).  Probable manganese exporter by similarity (see 3.A.3.10.7 and 3.A.3.10.8).

Eukaryota
Dictyosteliida
Putative Mn2+-ATPase of Dictyostelium discoideum
*3.A.3.10.10









Putative Mn2+-exporting P-type ATPase of 1343 aas.

Eukaryota
Albuginales
ATPase of Albugo laibachii
*3.A.3.10.11









This protein was reviously designated the functionally uncharacterized P-type ATPase 16 (FUPA16)  (Thever and Saier 2009).  Probable manganese exporter by similarity.

Eukaryota
Intramacronucleata
Putative Mn2+ ATPase of Tetrahymena thermophila (Q23QW3)
*3.A.3.10.12









P-type ATPase with N-terminal MACPF domain (TC# 1.C.39) of 1982 aas

Eukaryota
Intramacronucleata
MACPF-Mn2+ P-type ATPase of Tetrahymena thermophila
*3.A.3.10.13









This protein was previously designated the functionally uncharacterized P-type ATPase 17 (FUPA17) (Thever and Saier 2009), but it has been shown to be a Ca2+/Mn2+-exporting ATPase designated Cation-transporting ATPase 5 (Cta5 or ATP13A2) (Furune et al. 2008).

Eukaryota
Fungi
ATPase of Schizosaccharomyces pombe (O14022)
*3.A.3.10.14









This protein was previously designated the functionally uncharacterized P-type ATPase 18 (FUPA18 of 1491 aas) (Thever and Saier 2009).  It may be a Mn2+-ATPase (by similarity).

Eukaryota
Apicomplexa
FUPA18a of Cryptosporidium parvum (Q5CW06)
*3.A.3.10.15









This protein was previously designated the functionally uncharacterized P-type ATPase 19 (FUPA19 of 1807 aas) (Thever and Saier 2009).  The unusually large size and number of TMSs is unique to this protein.  Whether this is a consequence of an artifact of sequencing is not known.  It may be a Mn2+-ATPase (by similarity).

Eukaryota
Intramacronucleata
ATPase of Tetrahymena thermophilus
*3.A.3.10.16









This protein was previously designated the functionally uncharacterized P-type ATPase 20 (FUPA20) (Thever and Saier 2009).  It may be a Mn2+-exporting ATPase (by similarity).

Eukaryota
Intramacronucleata
ATPase of Tetrahymena thermophila (Q22V52)
*3.A.3.10.17









This protein was previously designated the functionally uncharacterized P-type ATPase 21 (FUPA21 of 1372 aas) (Thever and Saier 2009).  It may be a Mn2+-ATPase (by similarity).

Eukaryota
Bacillariophyta
ATPase of Thalassiosira pseudonana
*3.A.3.10.18









This protein was previously designated the functionally uncharacterized P-type ATPase 22 (FUPA22 of 1212-2393 aas) (Thever and Saier 2009).  It may be a Mn2+-exporting ATPase (by similarity).

Eukaryota
Apicomplexa
ATPase of Cryptosporidium parvum (Q5CTJ9)
*3.A.3.10.19









Mn2+-exporting ATPase, ATP13A1 of 1204 aas.  Defects cause Mn2+-dependent neurological disorders.  Orthologous to the yeast Mn2+-ATPase, Spf1 (Cohen et al. 2013). It is present in the endoplasmic reticulum while the other P5 ATPases, A2 - A5, are in overlapping compartments of the endosomal system (Sørensen et al. 2018). It complements the yeast ER ATPase, SPF1 (TC#3.A.3.10.3) although ATP13A2 - 5 do not, and unlike these latter proteins, it seems to have 12 (rather than 10) TMSs, with the two extra ones in an N-terminal domain (Sørensen et al. 2018). 

Eukaryota
Metazoa
ATP13A1 of Homo sapiens
*3.A.3.10.20









Probable divalent cation transporting ATPase 13A4, ATP13A4, of 1196 aas and 10 TMSs. This protein had been suggested to be a Mg2+ transporter, but the evidence is equivocal (Schäffers et al. 2018). It may be a Mn2+/Ca2+ exporter. This protein as well as ATP13A2 has been implicated in Parkinson's disease and autism spectrum disorder (Sørensen et al. 2018). ATPA2 - 5 are all in compartments of the endosomal system and all have 10 TMSs with overlapping functions, often in different amounts in different tissues (Sørensen et al. 2018).

Eukaryota
Metazoa
ATP13A4 of Homo sapiens
*3.A.3.10.21









Divalent cation transporting ATPase of 1207 aas and 9 putative TMSs, Catp-6.  C. elegans has three paralogues, Catp5, Catp6 and Catp7, with overlapping tissue expression patterns and functions (Zielich et al. 2018). 

Eukaryota
Metazoa
Catp-5 of Caenorhabditis elegans
*3.A.3.10.22









Manganese transporter of 1179 aas and 12 probable TMSs (Ticconi et al. 2004).  Mediates manganese transport into the endoplasmic reticulum. The ATPase activity is required for cellular manganese homeostasis. Plays an important role in pollen and root development through its impact on protein secretion and transport processes (Jakobsen et al. 2005). Functions together with LPR1 and LPR2 in a common pathway that adjusts root meristem activity to phosphate availability (Ticconi et al. 2009).

Eukaryota
Viridiplantae
PDR2 of Arabidopsis thaliana (Mouse-ear cress)
*3.A.3.23.1









Functionally uncharacterized P-type ATPase family 23 (FUPA23) (8 proteins from Actinomycetes; 650-802 aas) (Chan et al. 2010).

Bacteria
Actinobacteria
FUPA23a of Streptomyces coelicolor (Q9KXM5)
*3.A.3.23.2









Functionally uncharacterized P-type ATPase family 23 (FUPA23.2) (5 proteins from Firmicutes (778-1056aas; 10TMSs; type 2)).
Bacteria
Firmicutes
FUPA23b of Enterococcus faecalis (Q835V4)
*3.A.3.23.3









Functionally uncharacterized P-type ATPase family 23 (FUPA23) (2 proteins from Cyanobacteria (826-831aas; 10+MSs, type 2))
Bacteria
Cyanobacteria
FUPA23c of Trichodesmium erythraeum (Q10YH7)
*3.A.3.24.1









Functionally uncharacterized P-type ATPase family 24 (FUPA24) (6 proteins of Actinomycetes; 760-1625 aas) (Chan et al. 2010).

Bacteria
Actinobacteria
FUPA24a of Mycobacterium bovis (Q7U2U7)
*3.A.3.24.2









Functionally uncharacterized P-type ATPase family 24 (FUPA24) (1607aas); The first half is most like type I (Copper) ATPases, while the second half is most like type II ATPases (Ca2+).

Bacteria
Chloroflexi
FUPA24b of Thermomicrobium roseum (B9L3W5)
*3.A.3.24.3









Functionally uncharacterized P-type ATPase family 24 (FUPA24) (1430aas)

Bacteria
Proteobacteria
FUPA24c of Haliangium ochraceum (D0LKA4)
*3.A.3.24.4









Functionally uncharacterized P-type ATPase family 24 (FUPA24) (1446aas)

Bacteria
Proteobacteria
FUPA24d of Hahella chejuensis (ABC27339)
*3.A.3.25.1









Functionally uncharacterized P-type ATPase family 25 (FUPA25.1) (4 proteins from Actinomycetes; 645-776 aas) (Chan et al. 2010).

Bacteria
Actinobacteria
FUPA25a of Streptomyces coelicolor (Q9RJ01)
*3.A.3.25.2









Functionally uncharacterized P-type ATPase family 25 (FUPA25.2) (3 proteins from α- and β-proteobacteria; 617-759 aas). These proteins show greatest similarity with established families 5&6. Family 25 members have 6 TMSs and lack TMSs A&B. Some fairly close homologues have 7 TMSs.
Bacteria
Proteobacteria
FUPA25b of Sinorhizobium meliloti (Q92Z60)
*3.A.3.25.3









Functionally uncharacterized P-type ATPase family 25 (FUPA25.3) (2 proteins from firmicutes; 601-623 aas; 7TMSs and an extra putative N-terminal TMS).
Bacteria
Firmicutes
FUPA25c of Enterococcus faecalis (Q830Z1)
*3.A.3.25.4









P-type ATPase with a C-terminal hemeerythrin (Hr) domain (Traverso et al., 2010). The Hr domain binds two iron ions per monomer (a diiron center) and may provide a regulatory or more direct function in iron transport (Traverso et al., 2010).

Bacteria
Actinobacteria
P1B-5- ATPase of Acidothermus cellulolyticus (A0LQU2)
*3.A.3.27.1









Functionally uncharacterized P-type ATPase family 27 (FUPA27) (multiple proteins from α-, β- and γ- proteobacteria; 817-851aas) (Chan et al. 2010).

Bacteria
Proteobacteria
FUPA27a of Neisseria meningitidis (Q9JZI0)
*3.A.3.27.2









Functionally uncharacterized P-type ATPase family 27 (FUPA27), Lbi2 (

Bacteria
Spirochaetes
FUPA27b of Leptospira biflexa (B0STR2)
*3.A.3.27.3









Functionally uncharacterized ε-proteobacteria P-type ATPase

Bacteria
Proteobacteria
FUPA27c of Nitratiruptor sp. SB155-2 (A6Q500)
*3.A.3.27.4









The Cu2+ - ATPase, CtpA. Required for assembly of periplasmic and membrane embedded copper-dependent oxidases, but not for copper tolerance (Hassani, et al. 2010). Possibly CtpA delivers Cu2+ directly to the enzymes in the membrane rather than catalyzing transmembrane transport: similar to (3.A.3.27.1).

Bacteria
Proteobacteria
CtpA of Rubrivivax gelatinosus (Q5GCB0)
*3.A.3.27.5









Cu+ export ATPase, CopA2; provides copper for cytochrome oxidase assembly (González-Guerrero et al. 2010; Raimunda et al. 2013).

Bacteria
Proteobacteria
CopA2 of Pseudomonas aeruginosa
*3.A.3.27.6









Functionally uncharacterized P-type ATPase family 29 (FUPA29) (1 protein from a δ-proteobacterium, 798 aas) (Chan et al. 2010).

Bacteria
Proteobacteria
FUPA29a of Bdellovibrio bacteriovorus (Q6MK07)
*3.A.3.27.7









Functionally uncharacterized P-type ATPase family 29 (FUPA29) (2 proteins from flavobacteria; 792-795)

Bacteria
Bacteroidetes/Chlorobi group
FUPA29b of Flavobacterium johnsoniae (A5FGV9)
*3.A.3.30.1









Functionally uncharacterized P-type ATPase family 30 (FUPA30) (4 proteins from α-, β- and δ-proteobacteria; 825-896 aas) (Chan et al. 2010).

Bacteria
Proteobacteria
FUPA30a of Bdellovibrio bacteriovorus (Q6MPD9)
*3.A.3.30.2









Functionally uncharacterized P-type ATPase family 30 (FUPA30) (1 protein from Flavobacteria 838 aas)
Bacteria
Bacteroidetes/Chlorobi group
FUPA30b of Flavobacterium johnsoniae (A5FBE4)
*3.A.3.30.3









Functionally uncharacterized P-type ATPase family 30 (FUPA30), Lbi5 (1 protein in spirochetes)
Bacteria
Spirochaetes
FUPA30c of Leptospira biflexa (B0SLF7)
*3.A.3.30.4









Functionally uncharacterized P-type ATPase family 30 (FUPA30) (1 ptotein from cyanobacteria; 867 aas).
Bacteria
Cyanobacteria
FUPA30d of Anabaena variabilis (Q3M5P5)
*3.A.3.31.1









Functionally uncharacterized P-type ATPase family 31 (FUPA31) (3 proteins from γ-proteobacteria; 673-1068) (most closely related to FUPA32 homologues) (probably an active enzyme) (Chan et al. 2010).

Bacteria
Proteobacteria
FUPA31a of Methylococcus capsulatus (Q606V3)
*3.A.3.31.2









Functionally uncharacterized P-type ATPase family 31 (FUPA31b) (probably a pseudogene). Bears a C-terminal domain of the EcsC family (see 3.A.1.143.1) not found in other P-type ATPases.

Bacteria
Proteobacteria
FUPA31b of Methylococcus capsulatus (Q606U9)
*3.A.3.32.1









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (multiple proteins from α-, β-, γ-, δ- and ε-proteobacteria (690-720 aas) (Chan et al. 2010).

Bacteria
Proteobacteria
FUPA32a of Azoarcus sp. EbN1 (Q5P8C0)
*3.A.3.32.2









Probable heavy metal cation-transporting P-type ATPase, FUPA32.2 (718aas)
Bacteria
Actinobacteria
FUPA32b of Mycobacterium bovis (P0A503)
*3.A.3.32.3









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (many homologues in Firmicutes (704-730 aas))
Bacteria
Firmicutes
FUPA32c of Clostridium bartiettii (A6NST6)
*3.A.3.32.4









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (3 proteins from Fusobacteria) (735 aas)
Bacteria
Fusobacteria
FUPA32d of Fusobacterium nucleatum (Q8REB9)
*3.A.3.32.5









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (699 aas) (1 protein in Spirochetes)
Bacteria
Spirochaetes
FUPA32e of Treponema denticola (Q73QH0)
*3.A.3.32.6









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (2 proteins from Euryarchaeota)
Archaea
Euryarchaeota
FUPA32f of Methanobrevibacter smithii (A5UJX0)
*3.A.3.32.7









Functionally uncharacterized P-type ATPase family 32 (FUPA32) (several proteins from Verrucomicrobia)
Bacteria
Chlamydiae/Verrucomicrobia group
FUPA32g of Akkermansia muciniphila (B2UR24)
*3.A.3.32.8









Functionally uncharacterized P-type ATP family 32 (FUPA32) (several in cyanobacteria)
Bacteria
Cyanobacteria
FUPA32h of Thermosynechococcus elongatus (Q8DL41)