ID HVCN1_MOUSE Reviewed; 269 AA. AC Q3U2S8; Q9DCE4; DT 01-JUL-2008, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-2008, sequence version 2. DT 27-MAR-2024, entry version 134. DE RecName: Full=Voltage-gated hydrogen channel 1; DE AltName: Full=Hydrogen voltage-gated channel 1; DE Short=HV1 {ECO:0000303|PubMed:20026664}; DE AltName: Full=Voltage sensor domain-only protein {ECO:0000303|PubMed:16556803}; DE Short=mVSOP {ECO:0000303|PubMed:16556803}; GN Name=Hvcn1 {ECO:0000312|MGI:MGI:1921346}; Synonyms=Bts, Vsop; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J, and NOD; TISSUE=Kidney; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Salivary gland; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP TISSUE SPECIFICITY, DOMAIN, AND MUTAGENESIS OF ARG-201 AND ARG-207. RX PubMed=16556803; DOI=10.1126/science.1122352; RA Sasaki M., Takagi M., Okamura Y.; RT "A voltage sensor-domain protein is a voltage-gated proton channel."; RL Science 312:589-592(2006). RN [4] RP FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=19805063; DOI=10.1073/pnas.0905565106; RA Morgan D., Capasso M., Musset B., Cherny V.V., Rios E., Dyer M.J., RA DeCoursey T.E.; RT "Voltage-gated proton channels maintain pH in human neutrophils during RT phagocytosis."; RL Proc. Natl. Acad. Sci. U.S.A. 106:18022-18027(2009). RN [5] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [6] RP FUNCTION. RX PubMed=20026664; DOI=10.1084/jem.20091837; RA El Chemaly A., Okochi Y., Sasaki M., Arnaudeau S., Okamura Y., Demaurex N.; RT "VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and RT superoxide production by limiting cell depolarization and acidification."; RL J. Exp. Med. 207:129-139(2010). RN [7] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24415791; DOI=10.1189/jlb.0513251; RA El Chemaly A., Nunes P., Jimaja W., Castelbou C., Demaurex N.; RT "Hv1 proton channels differentially regulate the pH of neutrophil and RT macrophage phagosomes by sustaining the production of phagosomal ROS that RT inhibit the delivery of vacuolar ATPases."; RL J. Leukoc. Biol. 95:827-839(2014). RN [8] RP CAUTION. RX PubMed=37669933; DOI=10.1038/s41467-023-40855-0; RA Grahn E., Kaufmann S.V., Askarova M., Ninov M., Welp L.M., Berger T.K., RA Urlaub H., Kaupp U.B.; RT "Control of intracellular pH and bicarbonate by CO2 diffusion into human RT sperm."; RL Nat. Commun. 14:5395-5395(2023). RN [9] RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 220-266, FUNCTION, TRANSPORTER RP ACTIVITY, ACTIVITY REGULATION, SUBUNIT, COILED COIL, AND MUTAGENESIS OF RP ASN-231; 216-VAL--THR-218 AND 230-ILE--ILE-232. RX PubMed=22569364; DOI=10.1038/ncomms1823; RA Fujiwara Y., Kurokawa T., Takeshita K., Kobayashi M., Okochi Y., RA Nakagawa A., Okamura Y.; RT "The cytoplasmic coiled-coil mediates cooperative gating temperature RT sensitivity in the voltage-gated H(+) channel Hv1."; RL Nat. Commun. 3:816-816(2012). RN [10] RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 220-269, FUNCTION, TRANSPORTER RP ACTIVITY, SUBUNIT, AND COILED COIL. RX PubMed=23165764; DOI=10.1113/jphysiol.2012.243006; RA Fujiwara Y., Kurokawa T., Takeshita K., Nakagawa A., Larsson H.P., RA Okamura Y.; RT "Gating of the designed trimeric/tetrameric voltage-gated H+ channel."; RL J. Physiol. (Lond.) 591:627-640(2013). RN [11] RP X-RAY CRYSTALLOGRAPHY (3.45 ANGSTROMS) OF 73-215, FUNCTION, TRANSPORTER RP ACTIVITY, ACTIVITY REGULATION, SUBUNIT, AND TOPOLOGY. RX PubMed=24584463; DOI=10.1038/nsmb.2783; RA Takeshita K., Sakata S., Yamashita E., Fujiwara Y., Kawanabe A., RA Kurokawa T., Okochi Y., Matsuda M., Narita H., Okamura Y., Nakagawa A.; RT "X-ray crystal structure of voltage-gated proton channel."; RL Nat. Struct. Mol. Biol. 21:352-357(2014). CC -!- FUNCTION: Voltage-gated proton-selective channel that conducts outward CC proton currents in response to intracellular acidification. Lacks a CC canonical ion-channel pore domain and mediates proton permeability via CC its voltage sensor domain (PubMed:16556803, PubMed:19805063, CC PubMed:22569364, PubMed:23165764, PubMed:24584463). Provides for proton CC efflux that compensates for electron charge generated by NADPH oxidase CC activity either in the extracellular or phagosomal compartments, thus CC enabling the production of high levels of bactericidal reactive oxygen CC species during the respiratory burst (PubMed:19805063, PubMed:20026664, CC PubMed:24415791). Opens when the pH of airway surface liquid exceeds 7 CC and contributes to respiratory epithelial acid secretion to maintain pH CC in the mucosa (By similarity). {ECO:0000250|UniProtKB:Q96D96, CC ECO:0000269|PubMed:16556803, ECO:0000269|PubMed:19805063, CC ECO:0000269|PubMed:20026664, ECO:0000269|PubMed:22569364, CC ECO:0000269|PubMed:23165764, ECO:0000269|PubMed:24415791, CC ECO:0000269|PubMed:24584463}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000269|PubMed:16556803, ECO:0000269|PubMed:19805063, CC ECO:0000269|PubMed:22569364, ECO:0000269|PubMed:23165764, CC ECO:0000269|PubMed:24584463}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34980; CC Evidence={ECO:0000269|PubMed:16556803, ECO:0000269|PubMed:19805063, CC ECO:0000269|PubMed:22569364, ECO:0000269|PubMed:23165764}; CC -!- ACTIVITY REGULATION: The dimers display cooperative channel gating. The CC channel activity is inhibited by zinc ions. CC {ECO:0000269|PubMed:16556803, ECO:0000269|PubMed:19805063, CC ECO:0000269|PubMed:22569364, ECO:0000269|PubMed:24584463}. CC -!- SUBUNIT: Homodimer; each protomer forms its own proton conduction CC pathway. {ECO:0000269|PubMed:22569364, ECO:0000269|PubMed:23165764, CC ECO:0000269|PubMed:24584463}. CC -!- INTERACTION: CC Q3U2S8; Q3U2S8: Hvcn1; NbExp=3; IntAct=EBI-8401579, EBI-8401579; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q96D96}; CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane CC {ECO:0000250|UniProtKB:Q96D96}; Multi-pass membrane protein CC {ECO:0000255}. Cytoplasmic vesicle, phagosome membrane CC {ECO:0000269|PubMed:24415791}; Multi-pass membrane protein CC {ECO:0000255}. Cell projection, cilium, flagellum membrane CC {ECO:0000250|UniProtKB:Q96D96}; Multi-pass membrane protein CC {ECO:0000255}. Note=Detected within the principal piece of the sperm CC flagellum. {ECO:0000250|UniProtKB:Q96D96}. CC -!- TISSUE SPECIFICITY: Enriched in immune tissues, such as bone marrow, CC macrophages and spleen. {ECO:0000269|PubMed:16556803}. CC -!- DOMAIN: The voltage sensor domain (VSD, segments S1-S4) conducts both CC gating and ion permeation. The segment S4 is probably the voltage- CC sensor and is characterized by a series of positively charged amino CC acids at every third position. Unlike other voltage-gated ion channels CC it lacks the pore domain. {ECO:0000269|PubMed:16556803}. CC -!- DOMAIN: The C-terminal coiled coil region mediates homodimerization and CC cooperative channel gating. It is essential for normal subcellular CC localization. {ECO:0000269|PubMed:16556803}. CC -!- PTM: Phosphorylated in vitro by PRKCD. Phosphorylation may enhance CC channel gating. {ECO:0000250|UniProtKB:Q96D96}. CC -!- SIMILARITY: Belongs to the voltage-gated proton channel (VPC) CC (TC 1.A.51) family. {ECO:0000305}. CC -!- CAUTION: HVCN1 proton currents are missing in mouse sperm. CC {ECO:0000269|PubMed:37669933}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK002854; BAB22409.1; -; mRNA. DR EMBL; AK154880; BAE32899.1; -; mRNA. DR EMBL; AK155123; BAE33062.1; -; mRNA. DR EMBL; AK170422; BAE41787.1; -; mRNA. DR EMBL; BC021548; AAH21548.1; -; mRNA. DR CCDS; CCDS19644.1; -. DR RefSeq; NP_001035954.1; NM_001042489.2. DR RefSeq; NP_083028.1; NM_028752.3. DR RefSeq; XP_006530535.1; XM_006530472.2. DR RefSeq; XP_006530536.1; XM_006530473.1. DR PDB; 3VMX; X-ray; 1.45 A; A/B/C/D=220-266. DR PDB; 3VMY; X-ray; 1.47 A; A/B/C/D=220-269. DR PDB; 3VMZ; X-ray; 1.55 A; A/B/C/D=220-269. DR PDB; 3VN0; X-ray; 1.37 A; A/B/C/D=220-269. DR PDB; 3VYI; X-ray; 2.30 A; A/B/C/D/E/F/G/H/I/J/K/L=220-269. DR PDB; 3WKV; X-ray; 3.45 A; A=73-215. DR PDBsum; 3VMX; -. DR PDBsum; 3VMY; -. DR PDBsum; 3VMZ; -. DR PDBsum; 3VN0; -. DR PDBsum; 3VYI; -. DR PDBsum; 3WKV; -. DR AlphaFoldDB; Q3U2S8; -. DR SMR; Q3U2S8; -. DR BioGRID; 216489; 1. DR DIP; DIP-46134N; -. DR STRING; 10090.ENSMUSP00000098312; -. DR TCDB; 1.A.51.1.1; the voltage-gated proton channel (vpc) family. DR iPTMnet; Q3U2S8; -. DR PhosphoSitePlus; Q3U2S8; -. DR EPD; Q3U2S8; -. DR MaxQB; Q3U2S8; -. DR PaxDb; 10090-ENSMUSP00000072401; -. DR ProteomicsDB; 273325; -. DR Pumba; Q3U2S8; -. DR TopDownProteomics; Q3U2S8; -. DR Antibodypedia; 31051; 189 antibodies from 29 providers. DR DNASU; 74096; -. DR Ensembl; ENSMUST00000072602.14; ENSMUSP00000072401.8; ENSMUSG00000064267.14. DR Ensembl; ENSMUST00000100747.3; ENSMUSP00000098312.3; ENSMUSG00000064267.14. DR GeneID; 74096; -. DR KEGG; mmu:74096; -. DR UCSC; uc008zku.2; mouse. DR AGR; MGI:1921346; -. DR CTD; 84329; -. DR MGI; MGI:1921346; Hvcn1. DR VEuPathDB; HostDB:ENSMUSG00000064267; -. DR eggNOG; ENOG502RX8B; Eukaryota. DR GeneTree; ENSGT00940000159403; -. DR HOGENOM; CLU_076372_0_0_1; -. DR InParanoid; Q3U2S8; -. DR OMA; WEDEELH; -. DR OrthoDB; 5406176at2759; -. DR PhylomeDB; Q3U2S8; -. DR TreeFam; TF332056; -. DR Reactome; R-MMU-1222556; ROS and RNS production in phagocytes. DR Reactome; R-MMU-1300642; Sperm Motility And Taxes. DR Reactome; R-MMU-6798695; Neutrophil degranulation. DR BioGRID-ORCS; 74096; 3 hits in 76 CRISPR screens. DR ChiTaRS; Hvcn1; mouse. DR PRO; PR:Q3U2S8; -. DR Proteomes; UP000000589; Chromosome 5. DR RNAct; Q3U2S8; Protein. DR Bgee; ENSMUSG00000064267; Expressed in mesenteric lymph node and 108 other cell types or tissues. DR ExpressionAtlas; Q3U2S8; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISO:MGI. DR GO; GO:0016020; C:membrane; ISO:MGI. DR GO; GO:0034702; C:monoatomic ion channel complex; IEA:UniProtKB-KW. DR GO; GO:0030670; C:phagocytic vesicle membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0022843; F:voltage-gated monoatomic cation channel activity; ISO:MGI. DR GO; GO:0030171; F:voltage-gated proton channel activity; IDA:HGNC-UCL. DR GO; GO:0071467; P:cellular response to pH; ISS:UniProtKB. DR GO; GO:0071294; P:cellular response to zinc ion; ISS:UniProtKB. DR GO; GO:0032930; P:positive regulation of superoxide anion generation; ISO:MGI. DR GO; GO:1902600; P:proton transmembrane transport; IDA:HGNC-UCL. DR GO; GO:0051453; P:regulation of intracellular pH; IMP:UniProtKB. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; IMP:UniProtKB. DR GO; GO:0009268; P:response to pH; IDA:HGNC-UCL. DR GO; GO:0010043; P:response to zinc ion; IDA:HGNC-UCL. DR Gene3D; 1.20.5.170; -; 1. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 1. DR InterPro; IPR031846; Hvcn1. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR031844; VGPC1_C. DR InterPro; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR46480; F20B24.22; 1. DR PANTHER; PTHR46480:SF1; VOLTAGE-GATED HYDROGEN CHANNEL 1; 1. DR Pfam; PF00520; Ion_trans; 1. DR Pfam; PF16799; VGPC1_C; 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 1. DR Genevisible; Q3U2S8; MM. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cell projection; Cilium; Coiled coil; KW Cytoplasmic vesicle; Flagellum; Hydrogen ion transport; Immunity; KW Innate immunity; Ion channel; Ion transport; Membrane; Phosphoprotein; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; KW Voltage-gated channel. FT CHAIN 1..269 FT /note="Voltage-gated hydrogen channel 1" FT /id="PRO_0000342188" FT TOPO_DOM 1..96 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 97..117 FT /note="Helical; Name=Segment S1" FT TOPO_DOM 118..134 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 135..157 FT /note="Helical; Name=Segment S2" FT TOPO_DOM 158..165 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 166..186 FT /note="Helical; Name=Segment S3" FT TOPO_DOM 187..193 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 194..214 FT /note="Helical; Name=Segment S4" FT TOPO_DOM 215..269 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 46..79 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 221..261 FT /evidence="ECO:0000269|PubMed:22569364, FT ECO:0000269|PubMed:23165764" FT MOD_RES 29 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q96D96" FT MOD_RES 93 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96D96" FT MUTAGEN 201 FT /note="R->Q: Faster channel activation kinetics." FT /evidence="ECO:0000269|PubMed:16556803" FT MUTAGEN 207 FT /note="R->Q: Same activation kinetics as wild-type." FT /evidence="ECO:0000269|PubMed:16556803" FT MUTAGEN 216..218 FT /note="VKT->GGG: Impairs gating cooperativity." FT /evidence="ECO:0000269|PubMed:22569364" FT MUTAGEN 230..232 FT /note="INI->NIN: Slows channel activation." FT /evidence="ECO:0000269|PubMed:22569364" FT MUTAGEN 231 FT /note="N->L: No effect on channel activation kinetics." FT /evidence="ECO:0000269|PubMed:22569364" FT CONFLICT 66 FT /note="E -> A (in Ref. 1; BAE33062)" FT /evidence="ECO:0000305" FT HELIX 87..90 FT /evidence="ECO:0007829|PDB:3WKV" FT HELIX 96..120 FT /evidence="ECO:0007829|PDB:3WKV" FT HELIX 134..155 FT /evidence="ECO:0007829|PDB:3WKV" FT HELIX 164..184 FT /evidence="ECO:0007829|PDB:3WKV" FT HELIX 220..261 FT /evidence="ECO:0007829|PDB:3VN0" SQ SEQUENCE 269 AA; 31242 MW; B549CB553DEB6568 CRC64; MTSHDPKAVT RRTKVAPTKR MSRFLKHFTV VGDDYHTWNV NYKKWENEEE EEEPAPTSAE GEGNAEGPDA EAGSASTPRQ SLDFRSRLRK LFSSHRFQVI IICLVVLDAL LVLAELLLDL KIIEPDEQDY AVTAFHYMSF AILVFFMLEI FFKIFVFRLE FFHHKFEILD AFVVVVSFVL DLVLLFKSHH FEALGLLILL RLWRVARIIN GIIISVKTRS ERQILRLKQI NIQLATKIQH LEFSCSEKEQ EIERLNKLLK QNGLLGDVN //