HVCN1
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Voltage-gated hydrogen channel 1 is a protein that in humans is encoded by the HVCN1 gene.
Voltage-gated hydrogen channel 1 is a voltage-gated proton channel that has been shown to allow proton transport into phagosomes[1][2] and out of many types of cells including spermatozoa, electrically excitable cells and respiratory epithelial cells.[3] The proton-conducting HVCN1 channel has only transmembrane domains corresponding to the S1-S4 voltage sensing domains (VSD) of voltage-gated potassium channels and voltage-gated sodium channels.[4] Molecular simulation is consistent with a water-filled pore that can function as a "water wire" for allowing hydrogen bonded H+ to cross the membrane.[5][6] However, mutation of Asp112 in human Hv1 results in anion permeation, suggesting that obligatory protonation of Asp produces proton selectivity.[7] Quantum mechanical calculations show that the Asp-Arg interaction can produce proton selective permeation.[8] The HVCN1 protein has been shown to exist as a dimer with two functioning pores.[9][10] Like other VSD channels, HVCN1 channels conduct ions about 1000-fold slower than channels formed by tetrameric S5-S6 central pores.[11]
As a drug target
Small molecule inhibitors of the HVCN1 channel are being developed as chemotherapeutics and anti-inflammatory agents.[12]
References
- ↑ Murphy R, DeCoursey TE (August 2006). "Charge compensation during the phagocyte respiratory burst". Biochim. Biophys. Acta. 1757 (8): 996–1011. doi:10.1016/j.bbabio.2006.01.005. PMID 16483534.
- ↑ Capasso M, Bhamrah MK, Henley T, Boyd RS, Langlais C, Cain K, Dinsdale D, Pulford K, Khan M, Musset B, Cherny VV, Morgan D, Gascoyne RD, Vigorito E, DeCoursey TE, MacLennan IC, Dyer MJ (March 2010). "HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species". Nat. Immunol. 11 (3): 265–72. doi:10.1038/ni.1843. PMC 3030552. PMID 20139987.
- ↑ Capasso M, DeCoursey TE, Dyer MJ (January 2011). "pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1". Trends Cell Biol. 21 (1): 20–8. doi:10.1016/j.tcb.2010.09.006. PMC 3014425. PMID 20961760.
- ↑ Lee SY, Letts JA, MacKinnon R (April 2009). "Functional reconstitution of purified human Hv1 H+ channels". J. Mol. Biol. 387 (5): 1055–60. doi:10.1016/j.jmb.2009.02.034. PMC 2778278. PMID 19233200.
- ↑ Wood ML, Schow EV, Freites JA, White SH, Tombola F, Tobias DJ (February 2012). "Water wires in atomistic models of the Hv1 proton channel". Biochim. Biophys. Acta. 1818 (2): 286–93. doi:10.1016/j.bbamem.2011.07.045. PMC 3245885. PMID 21843503.
- ↑ Ramsey IS, Mokrab Y, Carvacho I, Sands ZA, Sansom MS, Clapham DE (July 2010). "An aqueous H+ permeation pathway in the voltage-gated proton channel Hv1". Nat. Struct. Mol. Biol. 17 (7): 869–75. doi:10.1038/nsmb.1826. PMC 4035905. PMID 20543828.
- ↑ Musset, B; Smith, SM; Rajan, S; Morgan, D; Cherny, VV; Decoursey, TE (23 October 2011). "Aspartate 112 is the selectivity filter of the human voltage-gated proton channel". Nature. 480 (7376): 273–7. doi:10.1038/nature10557. PMC 3237871. PMID 22020278.
- ↑ Dudev, T; Musset, B; Morgan, D; Cherny, VV; Smith, SM; Mazmanian, K; DeCoursey, TE; Lim, C (8 May 2015). "Selectivity Mechanism of the Voltage-gated Proton Channel, HV1". Scientific Reports. 5: 10320. doi:10.1038/srep10320. PMC 4429351. PMID 25955978.
- ↑ Gonzalez C, Koch HP, Drum BM, Larsson HP (January 2010). "Strong cooperativity between subunits in voltage-gated proton channels". Nat. Struct. Mol. Biol. 17 (1): 51–6. doi:10.1038/nsmb.1739. PMC 2935852. PMID 20023639.
- ↑ Tombola F, Ulbrich MH, Kohout SC, Isacoff EY (January 2010). "The opening of the two pores of the Hv1 voltage-gated proton channel is tuned by cooperativity". Nat. Struct. Mol. Biol. 17 (1): 44–50. doi:10.1038/nsmb.1738. PMC 2925041. PMID 20023640.
- ↑ DeCoursey TE (November 2008). "Voltage-gated proton channels: what's next?". J. Physiol. 586 (Pt 22): 5305–24. doi:10.1113/jphysiol.2008.161703. PMC 2655391. PMID 18801839.
- ↑ Hong L, Pathak MM, Kim IH, Ta D, Tombola F (January 2013). "Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains". Neuron. 77 (2): 274–87. doi:10.1016/j.neuron.2012.11.013. PMC 3559007. PMID 23352164.
Further reading
- Li SJ, Zhao Q, Zhou Q, et al. (2010). "The role and structure of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1". J. Biol. Chem. 285 (16): 12047–54. doi:10.1074/jbc.M109.040360. PMC 2852942. PMID 20147290.
- Musset B, Smith SM, Rajan S, et al. (2010). "Oligomerization of the voltage-gated proton channel". Channels (Austin). 4 (4): 260–5. doi:10.4161/chan.4.4.12789. PMC 3025757. PMID 20676047.
- Lishko PV, Botchkina IL, Fedorenko A, Kirichok Y (2010). "Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel". Cell. 140 (3): 327–37. doi:10.1016/j.cell.2009.12.053. PMID 20144758.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Musset B, Capasso M, Cherny VV, et al. (2010). "Identification of Thr29 as a critical phosphorylation site that activates the human proton channel Hvcn1 in leukocytes". J. Biol. Chem. 285 (8): 5117–21. doi:10.1074/jbc.C109.082727. PMC 2820736. PMID 20037153.
- Petheo GL, Orient A, Baráth M, et al. (2010). "Molecular and functional characterization of Hv1 proton channel in human granulocytes". PLoS ONE. 5 (11): e14081. doi:10.1371/journal.pone.0014081. PMC 2990768. PMID 21124855.
- Sasaki M, Takagi M, Okamura Y (2006). "A voltage sensor-domain protein is a voltage-gated proton channel". Science. 312 (5773): 589–92. doi:10.1126/science.1122352. PMID 16556803.
- Lee SY, Letts JA, Mackinnon R (2008). "Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1". Proc. Natl. Acad. Sci. U.S.A. 105 (22): 7692–5. doi:10.1073/pnas.0803277105. PMC 2409406. PMID 18509058.
- Suzuki Y, Yamashita R, Shirota M, et al. (2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Res. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
- Li SJ, Zhao Q, Zhou Q, Zhai Y (2009). "Expression, purification, crystallization and preliminary crystallographic study of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1". Acta Crystallographica Section F. 65 (Pt 3): 279–81. doi:10.1107/S1744309109003777. PMC 2650464. PMID 19255483.
- Suenaga T, Arase H, Yamasaki S, et al. (2007). "Cloning of B cell-specific membrane tetraspanning molecule BTS possessing B cell proliferation-inhibitory function". Eur. J. Immunol. 37 (11): 3197–207. doi:10.1002/eji.200737052. PMID 17948262.
- Iovannisci D, Illek B, Fischer H (2010). "Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T". J. Gen. Physiol. 136 (1): 35–46. doi:10.1085/jgp.200910379. PMC 2894549. PMID 20548053.
- Clark HF, Gurney AL, Abaya E, et al. (2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
- Musset B, Cherny VV, Morgan D, et al. (2008). "Detailed comparison of expressed and native voltage-gated proton channel currents". J. Physiol. 586 (10): 2477–86. doi:10.1113/jphysiol.2007.149427. PMC 2464343. PMID 18356202.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ramsey IS, Moran MM, Chong JA, Clapham DE (2006). "A voltage-gated proton-selective channel lacking the pore domain". Nature. 440 (7088): 1213–6. doi:10.1038/nature04700. PMC 4084761. PMID 16554753.
- Sakata S, Kurokawa T, Nørholm MH, et al. (2010). "Functionality of the voltage-gated proton channel truncated in S4". Proc. Natl. Acad. Sci. U.S.A. 107 (5): 2313–8. doi:10.1073/pnas.0911868107. PMC 2836681. PMID 20018719.