H+-translocating F-type ATPase. The loop-regions in subunits a and c that are implicated in H+ transport likely interact in a single structural domain which then functions in gating H+ release to the cytoplasm (Steed et al. 2014). Three different states that relate to rotation of the enzyme have been observed, with the central stalk's epsilon subunit in an extended autoinhibitory conformation in all three states (Sobti et al. 2016). The Fo motor consists of seven transmembrane helices and a decameric c-ring, and invaginations on either side of the membrane indicate the entry and exit channels for protons. The proton translocating subunit contains near parallel helices inclined by ~30 degrees to the membrane, a feature corresponding to rotary ATPases. This rotary ATPase subtype, the peripheral stalk, is resolved over the entire length of the complex, revealing the F1 attachment points and a coiled-coil that bifurcates toward the membrane with its helices separating to embrace subunit a from two sides (Sobti et al. 2016). Reversible beta/epsilon (stator/rotor) interactions may block rotation and thereby inhibit catalysis (Bulygin et al. 2004).
F-type ATPase of E. coli
Na+-translocating F-type ATPase/ATP synthase of 8 subunits. The Fo-a subunit plays a role in Na+ transport. It forms half channels that allow Na+ to enter and leave the buried carboxyl group on the Fo-c subunits. The essential Arg residue, R226, which faces the carboxyl group of Fo-c subunits in the middle of transmembrane helix 5 of the Fo-a subunit, separates the cytoplasmic side and periplasmic half-channels (Mitome et al. 2017). Residues that contribute to the integrity of the Na+ half channels have been identified; both half channels are present in the Fo-a subunit (Mitome et al. 2017).
F-type ATPase of Propionigenium modestum
H+-translocating F-type ATPase. Evidence of the proximity of ATP synthase subunit 6 is in proximity to the membrane in the supramolecular form (Velours et al., 2011). The structure of the intact monomeric ATP synthase from the fungus, Pichia angusta, has been solved by electron cryo-microscopy (Vinothkumar et al. 2016). The Mg2+ and Ca2+-dependent enzymes are both active, but exhibit quite different behaviors (Nesci et al. 2017). Dimerization is necessary to create the inner membrane folds (cristae) characteristic of mitochondria. Using cryo-electron microscopy, Guo et al. 2017 determined the structure of the dimeric FO complex from Saccharomyces cerevisiae at a resolution of 3.6 angstroms. The structure clarifies how the protons travel through the complex, how the complex dimerizes, and how the dimers bend the membrane to produce cristae. The crystal structure of the c-subunit ring with bound oligomycin revealed the inhibitor docked on the outer face of the proton-binding sites, deep in the transmembrane region (Zhou and Faraldo-Gómez 2018). A high resolution (3.7 Å) structure of the entire monomeric ATPase has been solved by cryo EM, suggesting how it is inhibited by oligomycin (Srivastava et al. 2018). Absence of the e and g subunits decreases conductance of the F-ATP synthase channel about tenfold. Ablation of the first TMS of subunit b, which creates a distinct lateral domain with e and g, further affected channel activity. Thus, F-ATP synthase e, g and b subunits create a domain within the membrane that is critical for the generation of the high-conductance channel that is a prime candidate for formation of the permeability transition pore (PTP). Subunits e and g are only present in eukaryotes and may have evolved to confer this novel function to F-ATP synthases (Carraro et al. 2018).
F-type ATPase of Saccharomyces cerevisiae Subunits ATP6; ATP8; ATP9; ATP1; ATP3; ATP16; ATP5; ATP2; ATP7; ATP14; ATP4; ATP15
The F-type ATPase of the ciliate, Tetrahymena thermophila (strain SB210). The eight established or putative ATPase subunits are provided. These are distantly related to subunits of other studied F-type ATPases (Balabaskaran Nina et al., 2010).Other associated proteins/subunits are presented by Balabaskaran Nina et al. (2010).
F-type ATPase of Tetrahymena thermophila strain SB210.
(1) F0 subunit 9 (subunit c) (76aas; 2 TMSs) (Q951A5)
(2) F1 %u03B4-subunit (OSCP) (219aas; 0 TMSs) (I7MMI7)
(3) F1 γ-subunit (299aas; 0 TMSs) (Q22Z05)
(4) F1 α-subunit (546aas; 0 TMSs) (Q24HY8)
(5) F1 β-subunit (497aas; 0 TMSs) (I7LZV1)
(6) hypothetical protein/putative F1 %u03B4 subunit (158aas; 0 TMSs) (Q22ZH1)
(7) hypothetical protein/putative F0 d subunit (234aas; 0 TMSs) (Q239R1)
(8) Ymf66/putative ATP synthase subunit a-like protein (446aas; 8 TMSs) (Q951C1)
The Na+-F1F0 ATP synthase. Has a hybrid rotor with 9 copies of an F0-like c-subunit with 1 ion binding site/2TMSs and 1 copy of a V0-like C1-subunit (with 1 ion binding site/4TMSs). The AtpI Mg2+ channel protein (TC# 1.A.77.10.4) is required for assembly of the hybrid rotor (Brandt et al. 2013).
F1F0-ATP synthase of Acetobacterium woodii
subunit size gene acc#
c2 82 atpE2 (Q59166)
c1 182 atpE1 (Q9RMB5)
α 502 atpA (P50000)
a 220 atpB (Q9RMB6)
δ 180 atpH (Q9RMB3)
b 184 atpF (Q9RMB4)
ε 133 atpC (P50009)
β 466 atpD (P50002)
γ 302 atpG (P50005)
F-type ATPase, AtpA-H
F-type ATPase of Parachlamydia acanthamoeba
AtpA, alpha, 504 aas
AtpB, a, 252 aas
AtpC, epsilon, 83 aas
AtpD, beta, 469 aas
AtpE, c, 77 aas
AtpF, b, 161 aas
AtpG, gamma, 286 aas
AtpH, delta, 183 aas
F-type ATPase. The enzyme can synthesize but not hydrolyze ATP due to the presence of the zeta inhibitor. The crystal structure is known (Morales-Rios et al. 2015). The complex that was crystallized contains the nine core proteins of the complete F-ATPase complex plus the zeta inhibitor protein. The formation of crystals depended upon the presence of bound bacterial cardiolipin and phospholipid molecules; when they were removed, the complex failed to crystallize.
F-type ATPase of Paracoccus denitrificans
Sodium (Na+)-pumping F-type ATPase. ATPase activity is stimulated by Na+ (Wiangnon et al. 2007), and Na+ transport in liposomes has been demostrated (Soontharapirakkul and Incharoensakdi 2010). The enzyme appears to play a role in salt tolerance (Soontharapirakkul et al. 2011). This halotolerant cyanobacterium has both a Na+- and a H+-pumping ATPase (see TC# 3.A.2.1.10). The sequence of the δ-subunit was not available at the time of entry.
Na+-ATPase of Aphanotheca halophytica
α, 514 aas
β, 470 aas
γ, 303 aas
δ, sequence not available
ε, 128 aas
a, 232 aas
b, 256 aas
c, 96 aa
H+-transporting F-type ATPase (Soontharapirakkul et al. 2011). This halotolerant cyanobacterium has two F-type ATPases, one pumping H+, and one pumping Na+ (see TC# 3.A.2.1.9).
Na+-ATPase of Aphanotheca halophytica
α, 505 aas
β, 484 aas
γ, 317 aas
δ, 187 aas
ε, 138 aas
a, 257 aas
b, 256 aas
b', 182 aas
c, 81 aas
F-type ATP synthase of 8 subunits common to other ATPases, and 9 subunits unique to the Chlorophyta. Near neighbor interactions of the membrane subunits have been measured (Sánchez-Vásquez et al. 2017). The spinich enzyme has been solved at 3.4 Å resolution by cryoEM (Hahn et al. 2018). The protein has 26 protein subunits, 17 of them membrane embedded. Its c-ring has 14 c subunits. Hahn et al. 2018 observed 3 chloroplast F1F0 conformations with the central rotor stalled in different positions, and ring rotation seemed to be divided into 3 unequal stteps. The stoichiometrically mismatched c-ring of F0s (composed of 8 to 17 c-subunits) and the 3-fold symmetric F1 head are flexibly coupled (Murphy et al. 2019). Based on cryo EM 2.7 Å resolution structures, 13 rotary states suggest a mechanism of the rotational movement, and the functions of novel subunits are proposed (Murphy et al. 2019).
F-type ATP synthase of Polytomella sp. Pringsheim 198.80 (Subunits b and ε are not available, and several of the Asa subunits are partial.
subunit α, 562 aas (A0ZW40)
subunit β, 574 aas (A0ZW41)
subunit γ, 317 aas (Q4LDE7)
subunit δ, 199 aas (D7P7X6)
subunit ε, not available
subunit a (OSCP)229 aas, 6 TMSs
subunit b (not available)
subunit c, 127 aas, 2 TMSs
subunit ASA1, 918 aas, 0 TMSs (Q85JD5)
subunit ASA2, 383 aas, 0 TMSs (D7P6B9)
subunit ASA3, 167 aas, 0 TMSs (D7P8N0)
subunit ASA4, 294 aas, 0 TMSs (D7NIZ2)
subunit ASA5, 123 aas and 0 TMSs (CBM40331.1)
subunit ASA6, 151 aas and 1 TMS (D7P897)
subunit ASA7, 190 aas, 0 TMSs (D8V7I2)
subunit ASA8, 89 aas, 1 TMS (D8V7I7)
F-type ATPase lacking a δ-subunit, but having another subunit, AtpR of 104 aas and 3 TMSs that may replace the δ-subunit. Has a c-subunit that shows the expected residues that comprise a Na+ binding site, so it may be a Na+ exporting ATPase. It is in a family of similar ATPases that all lack δ-subunits and have been called N-ATPases (Na+-transporting) (Dibrova et al. 2010). They appear to be subject to horizontal transfer and represent a second type of F-type ATPase, the other transporting protons. They are found in a variety of bacteria and archaea (Dibrova et al. 2010). The AtpQ protein may be a Mg2+ channel.
N-type ATPase of Methanosarcina barkeri
AtpD, β-subunit, 474 aas
AtpC, subunit, 139 aas
AtpR, extra subunit; possibly replacing the δ-subunit; 104 aas and 3 TMSs
AtpQ, the Mg2+ channel protein belonging to family 1.A.77.2 with 112 aas and 2 TMSs
AtpB, subunit a, 229 aas
AtpE, subunit c, 91 aas
AtpF, subunit b, 413 aas
AtpA. subunit α, 571 aas
AtpG, subunit γ, 301 aas
F-type ATPase/ATP synthase of T. brucei. The F1 domain has been studied and examined in 3-dimentions at low resolution, and in addition to the 5 usual subunits, it has an extra one, called p18 of 188 aas (UniProt acc # P0DPG4). p18 is present in three copies per complex. Suppression of expression of p18 affected in vitro growth of both the insect and infectious mammalian forms of T. brucei. It also reduced the levels of monomeric and multimeric F-ATPase complexes and diminished the in vivo hydrolytic activity of the enzyme (Gahura et al. 2018). The p18 subunit, identified only in the euglenozoa, associates with the external surface of each of the three α-subunits. Subunit p18 is a pentatricopeptide repeat (PPR) protein with three PPRs and appears to have no function in the catalytic mechanism of the enzyme (Montgomery et al. 2018). Inhibitors include furamidine (DB75), Pafuramidine (DB289), DB820 and DB829 (Meier et al. 2018).
F1-part of the F-type ATP synthase of Trypanosoma brucei
α, 584 aas, Q9GS23
β, 519 aas, Q9GPE9
γ, 305 aas, B0Z0F6
δ, 182 aas, P0DPG2
ε, 75 aas, P0DPG3
p18, 188 aas, P0PDPG4
The H+-translocating ATP synthase, Atp(Unc)ABCDEFGH. The 3-D structure has been determined by cryo-EM (Guo et al. 2019). The position of subunit epsilon shows how it is able to inhibit ATP hydrolysis while allowing ATP synthesis. The architecture of the membrane region shows how the ATP synthase is able to perform the same core functions as the equivalent, but more complicated, mitochondrial complex. The structures reveal the path of transmembrane proton translocation and provide a model for understanding decades of biochemical analysis, interrogating the roles of specific residues in the enzyme (Guo et al. 2019).
ATPase of Bacillus PS3
AtpA, UncA, α-subunit, 502 aas (P09219)
AtpB, UncB, a-subunit, 238 aas; 5 TMSs (P09218)
AtpC, UncC, ε-subunit, 132 aas (P07678)
AtpD, UncD, β-subunit, 473 aas (P07677)
AtpE, UncE, c-subunit, 72 aas; 2 TMSs (P00845)
AtpF, UncF, b-subunit, 163 aas; 1 TMS (P09221)
AtpG, UncG, γ-subunit, 286 aas (P09222)
AtpH, UncH, δ-subunit, 179 aas (P09220)
H+-translocating V-type ATPase. The 3-D structure is known (Lau and Rubinstein, 2012). More recently, Zhou and Sazanov 2019 solved cryo-EM structures of the intact Thermus thermophilus V/A-ATPase in three rotational states with two substates. These structures indicate substantial flexibility between V1 and Vo in a working enzyme, which results from mechanical competition between central shaft rotation and resistance from the peripheral stalks.
V-type ATPase of Thermus thermophilus
Na+-translocating V-type ATPase. The V-ATPase of E. hirae (EhV-ATPase) is composed of a soluble catalytic domain (V1; NtpA3-B3-D-G) and an integral membrane domain (V0; NtpI-K10) connected by a central and two peripheral stalks (NtpC, NtpD-G and NtpE-F) (see schematic figure 1 on pg. 60 of Muhammed et al., 2012). The membrane rotor ring of the Na+-ATPase consists of 10 NtpK subunits, which are homologs of the 16-KDa and 8-KDa proteolipids found in other V-ATPases and F-ATPases. Each NtpK subunit has four transmembrane alpha helices, with a sodium ion bound between helices 2 and 4 at a site buried deeply in the membrane that includes the essential residue glutamate-139 (Murata et al. 2005). This site is probably connected to the membrane surface by two half-channels in subunit NtpI, against which the ring rotates. Symmetry mismatch between the rotor and catalytic domains appears to be an intrinsic feature of both V- and F-ATPases (Murata et al. 2005). The EhV-ATPase is a Na+ pump in. Tsunoda et al. 2018 presented the entire structure of detergent-solubilized EhV-ATPase by single-particle cryo-EM using Zernike phase plates. The cryo-EM map showed one of three catalytic conformations. To further stabilize the originally heterogeneous structure caused by ATP hydrolysis, a peptide epitope tag system interfered with rotation of the central rotor by binding the Fab. As a result, the map unexpectedly showed another catalytic conformation of EhV-ATPase. These two conformations with and without Fab conversely coincided with those of the minor state 2 and the major state 1 of Thermus thermophilus V/A-ATPase, respectively. The most prominent feature in EhV-ATPase was the off-axis rotor, where the cytoplasmic V1 domain was connected to the Vo domain through the off-axis central rotor. Compared to the structure of ATP synthases, the larger size of the interface between the transmembrane a-subunit and c-ring of EhV-ATPase would be more advantageous for active ion pumping (Tsunoda et al. 2018).
V-type ATPase of Enterococcus hirae
NtpC (NtpP) (P43456)
NtpE (NtpO) (P43436)
NtpF (NtpL) (P43437)
NtpG (NtpQ) (P43455)
NtpI (NtpM) (P43439)
NtpK (NtpN) (P43457)
H+-translocating V-type ATPase. The d-subunit couples ATP hydrolysis to H+ transport (Owegi et al., 2006). The a subunit (Vph1p) most likely has an 8 TMS topology (Kartner et al. 2013; Knight and Behm 2012). Structures for three
rotational states show ten proteolipid subunits in the c-ring, setting the ATP:H+ ratio for proton
pumping. Long tilted TMSs in
the a-subunit interact with the c-ring. V-ATPase's membrane sector, Vo, has been implicated in functions including
membrane fusion and neurotransmitter release. Couoh-Cardel et al. 2016 reported that the purified V-ATPase c subunit ring (c-ring) forms dimers mediated by the c subunits'
cytoplasmic loops. Electrophysiological measurements of the c-ring reconstituted into a planar lipid
bilayer revealed a large unitary conductance of ~8.3 nS. A role of the
c-ring in membrane fusion and neuronal communication was suggested (Couoh-Cardel et al. 2016).
V-type ATPase of Saccharomyces cerevisiae
CUP5 (c1; VMA3)
VPH1 (a1; vacuole)
STV1 (a; Golgi) (P37296)
VMA9 (e) (Q3E7B6)
VMA16 (C'') (P23968)
The ubiquitous 14 subunit vacuolar H+-ATPase, V1/V0, has been implicated in various human diseases including osteopetrosis, renal tubule acidosis, and cancer (Hinton et al., 2009). The transmembrane enzyme, Ribonuclease kappa, RNASEK (137 aas; 2 TMSs; UniProt acc# Q6P5S7), closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses (Perreira et al. 2015). Cryo-EM allowed the construction of an atomic model, defining the enzyme's ATP:proton ratio as 3:10 and revealing a homolog of yeast subunit f in the membrane region, which appeared to be RNAseK (Abbas et al. 2020). The c ring encloses the transmembrane anchors for cleaved ATP6AP1/Ac45 and ATP6AP2/PRR, the latter of which is the (pro)renin receptor that, in other contexts, is involved in both Wnt signaling and the renin-angiotensin system that regulates blood pressure. This structure shows how ATP6AP1/Ac45 and ATP6AP2/PRR enable assembly of the enzyme's catalytic and membrane regions (Abbas et al. 2020).
14 subunits of the V-type ATPase of Homo sapiens
H -translocating V-type ATPase (Dettmer et al., 2006). The mung bean (Phaseolus aureus) subunits a and c (c'' and c") alone catalyze passive channel-mediated protein flux, but a c d did not (Ouyang et al., 2008). A 4 TMS c-subunit of Tamarix hispida (onion), almost identical to the c-subunit of the A. thaliana homologue, plays a stress tolerance role in response to salt, drought, UV, oxidation, heat, cold, and heavy metals (Gao et al. 2011). The VHA-H subunit is up-regluated upon high salt stress conditions (Yang et al. 2018).
V-type ATPase of Arabidopsis thaliana
H+-translocating V-type ATPase (Knight and Behm 2012). The c-subunit, ATP6V0C is upregulated by the drug against L. donovani, naloxonazine (De Muylder et al. 2016).
V-type ATPase of Mus musculus
H+-translocating V-type ATPase (Knight and Behm 2012).
V-type ATPase of Caenorhabditis elegans
V-type ATPase with 13 subunits
V-type ATPase of Paramecium tetraurelia
VatA1_1, 832 aas (Q6BFK1)
VatA2_1, 906 aas (Q3SDD1)
VatA3_1, 800 aas (Q3SDC9)
VatA4_1, 772 aas (Q3SDC7)
VatA5_1, 850 aas (Q3SDC6)
VatA6_1, 831 aas (Q3SDC5)
VatA7_1, 768 aas (Q3SDC3)
VatA8_1, 793 aas (Q6BGD8)
VatA9_1, 860 aas (Q3SDB6)
Vat beta subunit, 511 aas (Q3SEA2)
VhaA1/A2, 618 aas (Q4UJ82)
VhaC5/C6, 165 aas (Q4UJ88)
VhaF1, 127 aas (Q4UJ86)
subunit c of the H+-pumping V-type ATPase. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).
c-subunit of Trypanosoma brucei
H+-translocating A-type ATPase (Pisa et al., 2007b).
A-type ATPase of Methanosarcina mazei AhaABCDEFG
The A1A0-ATP synthase, Aha ABCDEFHIK or MbbrA1A0 (AhaC has 4 TMSs; each hairpin has a complete Na+-binding motif. Can use Na+ or H+ to synthesize ATP (McMillan et al., 2011).
Aha ABCDEFHIK of Methanobrevibacter ruminantium
Aha A (D3E1Z1)
Aha B (D3E1Z2)
Aha C (D3E1Y9)
Aha D (D3E1Z3)
Aha E (D3E1Y8)
Aha F (D3E1Z0)
Aha H (D3E1Y5)
Aha I (D3E1Y6)
Aha K (D3E1Y7)
Two sector V-type ATPase or ATP synthase of 12 subunits.
V-type ATPase of Treponema pallidum
AtpI1, AtpD1, AtpB1, AtpA1, NtpK, AtpD2, AtpB2, AtpA2, AtpF, NtpI2, plus two uncharacterized proteins.