TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.A.51.1.1









The voltage-gated proton channel, mVSOP (269 aas and 2 TMSs) (Sasaki et al., 2006).  A hydrophobic plug functions as the gate (Chamberlin et al. 2013). Gating current measurements revealed that voltage-sensor (VS) activation and proton-selective aqueous conductance opening are thermodynamically distinct steps in the Hv1 activation pathway and showed that pH changes directly alter VS activation. Gating cooperativity, pH-dependent modulation, and a high degree of H+ selectivity have been demonstrated (De La Rosa and Ramsey 2018).

Eukaryota
Metazoa, Chordata
mVSOP of Mus musculus (Q9DCE4)
1.A.51.1.2









The voltage-gated proton channel, Hv1, Hv1, HV1 or HVCN1 (273 aas) (Ramsey et al., 2006). Thr29 is a phosphorylation site that activates the HVCN1 channel in leukocytes (Musset et al., 2010). The condctivity pore has been delineated and depends of a carboxyl group (Asp or Glu) in the channel (Morgan et al. 2013). The four transmembrane helices sense voltage and the pH gradient, and conduct protons exclusively. Selectivity is achieved by the unique ability of H3O+ to protonate an Asp-Arg salt bridge. Pathognomonic sensitivity of gating to the pH gradient ensures HV1 channel opening only when acid extrusion will result, which is crucial to its biological functions (DeCoursey 2015). An exception occurs in dinoflagellates (see 1.A.51.1.4) in which H+ influx through HV1 triggers a bioluminescent flash. The gating mechanism of Hv1, cooperativity within dimers and the sensitivity to metal ions have been reviewed (Okamura et al. 2015). How this channel is activated by cytoplasmic [H+] and depolarization of the membrane potential has been proposed by Castillo et al. 2015. The extracellular ends of the first transmembrane segments form the intersubunit interface that mediates coupling between binding sites, while the coiled-coil domain does not directly participate in the process (Hong et al. 2015). Deep water penetration through hHv1 has been observed, suggesting a highly focused electric field, comprising two helical turns along the fourth TMS. This region likely contains the H+ selectivity filter and the conduction pore. A 3D model offers an explicit mechanism for voltage activation based on a one-click sliding helix conformational rearrangement (Li et al. 2015).  Trp-207 enables four characteristic properties: slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and ΔpH-dependent gating (Cherny et al. 2015).  The native Hv structure is a homodimer, with the two channel subunits functioning cooperatively (Okuda et al. 2016).  Segment S3 plays a role in activating gating (Sakata et al. 2016).  Two sites have been identified: one is the binding pocket of 2GBI (accessible to ligands from the intracellular side); the other is located at the exit site of the proton permeation pathway (Gianti et al. 2016).   Crystal structures of Hv1 dimeric channels revealed that the primary contacts between the two monomers are in the C-terminal domain (CTD), which forms a coiled-coil structure. Molecular dynamics (MD) simulations of full-length and truncated CTD models revealed a strong contribution of the CTD to the packing of the TMSs (Boonamnaj and Sompornpisut 2018).  Histidine-168 is essential for the ΔpH-dependent gating (Cherny et al. 2018). Proton transfer in Hv1 utilizes a water wire, and does not require transient protonation of a conserved aspartate in the S1 transmembrane helix (Bennett and Ramsey 2017).  Hv1 channels are present in bull spermatozoa, and these regulate sperm functions like hypermotility, capacitation and acrosome reaction through a complex interplay between different pathways involving cAMP, PKC, and Catsper (Mishra et al. 2019). A zinc binding site influences gating configurations of HV1 (Cherny et al. 2020). The discovery and validation of Hv1 proton channel inhibitors with onco-therapeutic potential have been described (El Chemaly et al. 2023). Nitrates can stimulate the biosynthesis of hydrophilic yellow pigments (HYPs) in Monascus ruber (Huang et al. 2023). ATP influences Hv1 activity via direct molecular interactions, and its functional characteristics are required for the physiological activity of Hv1 (Kawanabe et al. 2023). Trp207 regulates voltage-dependent activation of the human Hv1 proton channel. (Zhang et al. 2024).

Eukaryota
Metazoa, Chordata
Hv1 of Homo sapiens (Q96D96)
1.A.51.1.3









Voltage-gated proton channel, HvCN1; VSOP; VSX1 (Sasaki et al., 2006).  Exhibits voltage and pH-dependent gating as well as Zn2+-reactivity. In the dimeric strcuture, each subumit has a proton channel. TMS4 appears to be the voltage sensor.  Subunit cooperativity has been demonstrated (Gonzalez et al. 2010).  The activation of the Hv1 voltage sensor is governed by electrostatic-hydrophobic interactions, and S4 arginines, N264 and the selectivity filter (D160) are essential in the Ciona-Hv1 to understand the trapping of the voltage sensor (Fernández et al. 2023).

 

Eukaryota
Metazoa, Chordata
HvCN1 of Ciona intestinalis (Q1JV40)
1.A.51.1.4









Voltage-gated proton-specific monomeric channel, kHv1. Activated by depolarization; functions in signaling and excitability to trigger bioluminescence (Smith et al., 2011).  Hv1 most likely forms an internal water wire for selective proton transfer, and interactions between water molecules and S4 arginines may underlie coupling between voltage- and pH-gradient sensing (Ramsey et al. 2010).

Eukaryota
kHv1 of Karlodinium veneficum (G5CPN9)
1.A.51.1.5









Proton channel protein, NpHv1 of 239 aas and 4 TMSs.  Proton selectivity, and pH- and voltage-dependent gating have been demoonstrated. Mutations in the first transmembrane segment at position 66 (Asp66), the presumed selectivity filter, led to a loss of proton-selective conduction (Chaves et al. 2016).

Eukaryota
Metazoa, Arthropoda
NpHv1 of Nicoletia phytophila
1.A.51.1.6









Hv1 proton channel of 223 aas and 4 TMSs. It's proton transport activity has been demonstrated (Zhao and Tombola 2021).

Eukaryota
Fungi, Basidiomycota
Hv1 of Suillus luteus
1.A.51.1.7









Proton channel protein of 211 aas and 4 TMSs. It's proton channel activity has been demonstrated and shown to differ in its regulation from the fungal channel with TC# 1.A..51.1.6 (Zhao and Tombola 2021). The presence of protein sequences corresponding to such channels were demonstrated in all four types of fungi (Zhao and Tombola 2021).

fungi
Fungi, Ascomycota
Hv1 of Aspergillus oryzae
1.A.51.2.1









The voltage-sensor containing phosphatase, VSP, of 576 aas and 4 TMSs N-terminal to the phosphatase domain. The enzyme region of VSP contains the phosphatase and C2 domains, is structurally similar to the tumor suppressor phosphatase PTEN, and catalyzes the dephosphorylation of phosphoinositides. The transmembrane voltage sensor is connected to the phosphatase through a short linker region, and phosphatase activity is induced upon membrane depolarization (Zhang et al. 2018). The coupling between the two domains has been studied (Sakata et al. 2017). Membrane depolarization activates the phosphatase activity of the enzyme, presumably via electroconformational coupling between the sensor domain and the enzyme (Sanders and Hutchison 2018). Both the phosphatase domain and the C2 domain move with similar timing upon membrane depolarization (Sakata and Okamura 2018). Four states are visited sequentially in a stepwise manner during voltage activation, each step translocating one arginine or the equivalent of approximately 1 e0 across the membrane electric field, yielding a transfer of approximately 3 e0 charges in total for the complete process (Shen et al. 2022).

 

Eukaryota
Metazoa, Chordata
VSP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis)
1.A.51.2.2









Voltage-sensing phosphatase-2, VSP2, isoform X1, of 509 aas with 4 N-terminal TMSs that comprise the voltage sensor. 

Eukaryota
Metazoa, Chordata
VSP2 of Xenopus laevis (African clawed frog)
1.A.51.2.3









Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase, TPTE2, isoform gamma of522 aas and 4 TMSs.

Eukaryota
Metazoa, Chordata
TPTE2 of Homo sapiens
1.A.51.2.4









Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase, PTEN of 403 aas and 1 N-terminal TMS. It acts as a dual-specificity lipid phosphatase and a protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (Li and Sun 1997). It is involved in the regulation of synaptic function in excitatory hippocampal synapses, and is recruited to the postsynaptic membrane upon NMDA receptor activation. It is also required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression. Its expression is not affected by smoking of cigarettes or e-cigarettes (Shabestari et al. 2023).

Eukaryota
Metazoa, Chordata
PTEN of Homo sapiens