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1.A.25.2.1
Pannexin-1 (PANX1) has been reported to form functional, single membrane, cell surface channels (Penuela et al., 2007). Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex (Locovei et al., 2007). It can catalyze ATP release from cells (Huang and Roper, 2010) and promote ATP signalling in mice (Suadicani et al. 2012). It also promotes acetaminophen liver toxicity by allowing it to enter the cell (Maes et al. 2016).  Pannexin1 and pannexin2 channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 constitutes the large conductance cation channel of cardiac myocytes (Kienitz et al., 2011). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). Single cysteines in the extracellular and transmembrane regions modulate pannexin 1 channel function (Bunse et al., 2011).  Spreading depression triggers migraine headaches by activating neuronal pannexin1 (panx1) channels  (Karatas et al. 2013).  The channel in the mouse orthologue opens upon apoptosis (Spagnol et al. 2014). Transports ATP out of the cell since L-carbenoxolone (a Panx1 channel blocker) inhibits ATP release from the nasal mucosa, but flufenamic acid (a connexin channel blocker) and gadolinium (a stretch-activated channel blocker) do not (Ohbuchi et al. 2014). CALHM1 (TC#1.N.1.1.1) and PANX1 both play roles in ATP release and downstream ciliary beat frequency modulation following a mechanical stimulus in airway epithelial cells (Workman et al. 2017). Pannexin1 may play a role in the pathogenesis of liver disease (Willebrords et al. 2018). Inhibition of pannexin1 channel opening may provide a novel approach for the treatment of drug (acetaminophen-induced)-induced hepatotoxicity (Maes et al. 2017). Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. It is highly expressed in HDLECs and is required for in vitro lymphangiogenesis (Boucher et al. 2018). cryo-EM structure of a pannexin 1 reveals unique motifs for ion selection and inhibition. The cryo-EM structure of a pannexin 1 revealed unique motifs for ion selection and inhibition (Michalski et al. 2020). In another study, Deng et al. 2020 obtained near-atomic-resolution structures of human and frog PANX1 determined by cryo-EM that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide. An extracellular tryptophan ring located at the outer pore created a constriction site, potentially functioning as a molecular sieve that restricts the sizes of permeable substrates. Pannexin 1 channels in renin-expressing cells influence renin secretion and homeostasis (DeLalio et al. 2020). Structures of human pannexin 1 have revealed ion pathways and mechanism of gating (Ruan et al. 2020). PANX1 is critical for functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. Ruan et al. 2020 presented several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 Å, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. A gating mechanism was revealed that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. A carbenoxolone (a channel blocker)-binding site is embraced by W74 in the extracellular entrance. A gap-junction-like structure was observed as expected (Yen and Saier 2007; Chou et al. 2017). Navis et al. 2020 provided a review of the literature on Panx1 structural biology and known pharmacological agents that target it. The R217H mutation perturbs the conformational flexibility of the C-terminus, leading to channel dysfunction (Purohit and Bera 2021). Panx1 plays decisive roles in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It exerts some of these roles in the context of purinergic signaling by providing a transmembrane pathway for ATP, but Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability (Mim et al. 2021).

Accession Number:Q96RD7
Protein Name:Pannexin-1 aka PANX1 aka MRS1
Length:426
Molecular Weight:48059.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate ATP

Cross database links:

Genevestigator: Q96RD7
eggNOG: prNOG11535
RefSeq: NP_056183.2   
Entrez Gene ID: 24145   
Pfam: PF00876   
Drugbank: Drugbank Link   
OMIM: 608420  gene
KEGG: hsa:24145   

Gene Ontology

GO:0032059 C:bleb
GO:0005921 C:gap junction
GO:0016021 C:integral to membrane
GO:0005102 F:receptor binding
GO:0006812 P:cation transport
GO:0050718 P:positive regulation of interleukin-1 beta s...

References (4)

[1] “The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins.”  Baranova A.et.al.   15028292
[2] “The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.”  Clark H.F.et.al.   12975309
[3] “Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries.”  Otsuki T.et.al.   16303743
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
Structure:
6LTN   6LTO   6M02   6M66   6M67   6M68   6V6D   6WBF   6WBG   6WBI   [...more]

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MAIAHLATEY VFSDFLLKEP TEPKFKGLRL ELAVDKMVTC IAVGLPLLLI SLAFAQEISI 
61:	GTQISCFSPS SFSWRQAAFV DSYCWAAVQQ KNSLQSESGN LPLWLHKFFP YILLLFAILL 
121:	YLPPLFWRFA AAPHICSDLK FIMEELDKVY NRAIKAAKSA RDLDMRDGAC SVPGVTENLG 
181:	QSLWEVSESH FKYPIVEQYL KTKKNSNNLI IKYISCRLLT LIIILLACIY LGYYFSLSSL 
241:	SDEFVCSIKS GILRNDSTVP DQFQCKLIAV GIFQLLSVIN LVVYVLLAPV VVYTLFVPFR 
301:	QKTDVLKVYE ILPTFDVLHF KSEGYNDLSL YNLFLEENIS EVKSYKCLKV LENIKSSGQG 
361:	IDPMLLLTNL GMIKMDVVDG KTPMSAEMRE EQGNQTAELQ GMNIDSETKA NNGEKNARQR 
421:	LLDSSC