LRC8A_HUMAN
ID LRC8A_HUMAN Reviewed; 810 AA.
AC Q8IWT6; Q6UXM2; Q8NCI0; Q9P2B1;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Volume-regulated anion channel subunit LRRC8A {ECO:0000305};
DE AltName: Full=Leucine-rich repeat-containing protein 8A {ECO:0000303|PubMed:22532330};
DE Short=HsLRRC8A {ECO:0000303|PubMed:30127360};
DE AltName: Full=Swelling protein 1 {ECO:0000303|PubMed:24725410};
GN Name=LRRC8A {ECO:0000303|PubMed:22532330, ECO:0000312|HGNC:HGNC:19027};
GN Synonyms=KIAA1437 {ECO:0000303|PubMed:10718198},
GN LRRC8 {ECO:0000303|PubMed:14660746}, SWELL1 {ECO:0000303|PubMed:24725410};
GN ORFNames=UNQ221/PRO247 {ECO:0000303|PubMed:12975309};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, CHROMOSOMAL
RP TRANSLOCATION, AND INVOLVEMENT IN AGM5.
RX PubMed=14660746; DOI=10.1172/jci200318937;
RA Sawada A., Takihara Y., Kim J.Y., Matsuda-Hashii Y., Tokimasa S.,
RA Fujisaki H., Kubota K., Endo H., Onodera T., Ohta H., Ozono K., Hara J.;
RT "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in
RT humans.";
RL J. Clin. Invest. 112:1707-1713(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [5]
RP PROTEIN SEQUENCE OF 1-8; 483-492; 534-541 AND 735-749, ACETYLATION AT
RP MET-1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Lung fibroblast;
RA Bienvenut W.V., Pchelintsev N., Adams P.D.;
RL Submitted (OCT-2009) to UniProtKB.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 239-810.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 259-810.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP DOMAINS LEUCINE-RICH REPEATS.
RX PubMed=15183935; DOI=10.1016/j.molimm.2004.04.001;
RA Smits G., Kajava A.V.;
RT "LRRC8 extracellular domain is composed of 17 leucine-rich repeats.";
RL Mol. Immunol. 41:561-562(2004).
RN [9]
RP IDENTIFICATION.
RX PubMed=22532330; DOI=10.1002/bies.201100173;
RA Abascal F., Zardoya R.;
RT "LRRC8 proteins share a common ancestor with pannexins, and may form
RT hexameric channels involved in cell-cell communication.";
RL Bioessays 34:551-560(2012).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-217, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-217, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-215 AND SER-217, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP THR-44.
RX PubMed=24725410; DOI=10.1016/j.cell.2014.03.024;
RA Qiu Z., Dubin A.E., Mathur J., Tu B., Reddy K., Miraglia L.J.,
RA Reinhardt J., Orth A.P., Patapoutian A.;
RT "SWELL1, a plasma membrane protein, is an essential component of volume-
RT regulated anion channel.";
RL Cell 157:447-458(2014).
RN [15]
RP SUBCELLULAR LOCATION, TOPOLOGY, INTERACTION WITH LRRC8D, AND SUBUNIT.
RX PubMed=24782309; DOI=10.1074/jbc.m114.571257;
RA Lee C.C., Freinkman E., Sabatini D.M., Ploegh H.L.;
RT "The protein synthesis inhibitor blasticidin S enters mammalian cells via
RT leucine-rich repeat-containing protein 8D.";
RL J. Biol. Chem. 289:17124-17131(2014).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, INTERACTION
RP WITH LRRC8B; LRRC8C; LRRC8D AND LRRC8E, TOPOLOGY, GLYCOSYLATION, AND
RP MUTAGENESIS OF ASN-66 AND ASN-83.
RX PubMed=24790029; DOI=10.1126/science.1252826;
RA Voss F.K., Ullrich F., Muench J., Lazarow K., Lutter D., Mah N.,
RA Andrade-Navarro M.A., von Kries J.P., Stauber T., Jentsch T.J.;
RT "Identification of LRRC8 heteromers as an essential component of the
RT volume-regulated anion channel VRAC.";
RL Science 344:634-638(2014).
RN [17]
RP FUNCTION.
RX PubMed=26530471; DOI=10.15252/embj.201592409;
RA Planells-Cases R., Lutter D., Guyader C., Gerhards N.M., Ullrich F.,
RA Elger D.A., Kucukosmanoglu A., Xu G., Voss F.K., Reincke S.M., Stauber T.,
RA Blomen V.A., Vis D.J., Wessels L.F., Brummelkamp T.R., Borst P.,
RA Rottenberg S., Jentsch T.J.;
RT "Subunit composition of VRAC channels determines substrate specificity and
RT cellular resistance to Pt-based anti-cancer drugs.";
RL EMBO J. 34:2993-3008(2015).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=26824658; DOI=10.1016/j.cell.2015.12.031;
RA Syeda R., Qiu Z., Dubin A.E., Murthy S.E., Florendo M.N., Mason D.E.,
RA Mathur J., Cahalan S.M., Peters E.C., Montal M., Patapoutian A.;
RT "LRRC8 proteins form volume-regulated anion channels that sense ionic
RT strength.";
RL Cell 164:499-511(2016).
RN [19]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=28193731; DOI=10.1242/jcs.196253;
RA Lutter D., Ullrich F., Lueck J.C., Kempa S., Jentsch T.J.;
RT "Selective transport of neurotransmitters and modulators by distinct
RT volume-regulated LRRC8 anion channels.";
RL J. Cell Sci. 130:1122-1133(2017).
RN [20]
RP DOMAIN, AND MUTAGENESIS OF GLU-6.
RX PubMed=29925591; DOI=10.1074/jbc.ra118.002853;
RA Zhou P., Polovitskaya M.M., Jentsch T.J.;
RT "LRRC8 N termini influence pore properties and gating of volume-regulated
RT anion channels (VRACs).";
RL J. Biol. Chem. 293:13440-13451(2018).
RN [21]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=29769723; DOI=10.1038/s41586-018-0134-y;
RA Deneka D., Sawicka M., Lam A.K.M., Paulino C., Dutzler R.;
RT "Structure of a volume-regulated anion channel of the LRRC8 family.";
RL Nature 558:254-259(2018).
RN [22]
RP FUNCTION.
RX PubMed=29371604; DOI=10.1038/s41467-017-02664-0;
RA Kang C., Xie L., Gunasekar S.K., Mishra A., Zhang Y., Pai S., Gao Y.,
RA Kumar A., Norris A.W., Stephens S.B., Sah R.;
RT "SWELL1 is a glucose sensor regulating beta-cell excitability and systemic
RT glycaemia.";
RL Nat. Commun. 9:367-367(2018).
RN [23]
RP FUNCTION.
RX PubMed=31270356; DOI=10.1038/s41598-019-45939-w;
RA Lenk G.M., Park Y.N., Lemons R., Flynn E., Plank M., Frei C.M., Davis M.J.,
RA Gregorka B., Swanson J.A., Meisler M.H., Kitzman J.O.;
RT "CRISPR knockout screen implicates three genes in lysosome function.";
RL Sci. Rep. 9:9609-9609(2019).
RN [24]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-103.
RX PubMed=33171122; DOI=10.1016/j.molcel.2020.10.021;
RA Lahey L.J., Mardjuki R.E., Wen X., Hess G.T., Ritchie C., Carozza J.A.,
RA Boehnert V., Maduke M., Bassik M.C., Li L.;
RT "LRRC8A:C/E heteromeric channels are ubiquitous transporters of cGAMP.";
RL Mol. Cell 0:0-0(2020).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF 706-LEU-LEU-707.
RX PubMed=33139539; DOI=10.1073/pnas.2016539117;
RA Li P., Hu M., Wang C., Feng X., Zhao Z., Yang Y., Sahoo N., Gu M., Yang Y.,
RA Xiao S., Sah R., Cover T.L., Chou J., Geha R., Benavides F., Hume R.I.,
RA Xu H.;
RT "LRRC8 family proteins within lysosomes regulate cellular osmoregulation
RT and enhance cell survival to multiple physiological stresses.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:29155-29165(2020).
RN [26] {ECO:0007744|PDB:6DJB}
RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS), FUNCTION, DISULFIDE
RP BONDS, DOMAIN, AND MUTAGENESIS OF THR-5 AND ARG-103.
RX PubMed=30095067; DOI=10.7554/elife.38461;
RA Kefauver J.M., Saotome K., Dubin A.E., Pallesen J., Cottrell C.A.,
RA Cahalan S.M., Qiu Z., Hong G., Crowley C.S., Whitwam T., Lee W.H.,
RA Ward A.B., Patapoutian A.;
RT "Structure of the human volume regulated anion channel.";
RL Elife 7:0-0(2018).
RN [27] {ECO:0007744|PDB:5ZSU}
RP STRUCTURE BY ELECTRON MICROSCOPY (4.25 ANGSTROMS), DISULFIDE BONDS, AND
RP DOMAIN.
RX PubMed=30127360; DOI=10.1038/s41594-018-0109-6;
RA Kasuya G., Nakane T., Yokoyama T., Jia Y., Inoue M., Watanabe K.,
RA Nakamura R., Nishizawa T., Kusakizako T., Tsutsumi A., Yanagisawa H.,
RA Dohmae N., Hattori M., Ichijo H., Yan Z., Kikkawa M., Shirouzu M.,
RA Ishitani R., Nureki O.;
RT "Cryo-EM structures of the human volume-regulated anion channel LRRC8.";
RL Nat. Struct. Mol. Biol. 25:797-804(2018).
RN [28]
RP VARIANT HIS-545.
RX PubMed=30135305; DOI=10.1172/jci.insight.99767;
RA Bao J., Perez C.J., Kim J., Zhang H., Murphy C.J., Hamidi T., Jaubert J.,
RA Platt C.D., Chou J., Deng M., Zhou M.H., Huang Y., Gaitan-Penas H.,
RA Guenet J.L., Lin K., Lu Y., Chen T., Bedford M.T., Dent S.Y.,
RA Richburg J.H., Estevez R., Pan H.L., Geha R.S., Shi Q., Benavides F.;
RT "Deficient LRRC8A-dependent volume-regulated anion channel activity is
RT associated with male infertility in mice.";
RL JCI Insight 3:0-0(2018).
CC -!- FUNCTION: Essential component of the volume-regulated anion channel
CC (VRAC, also named VSOAC channel), an anion channel required to maintain
CC a constant cell volume in response to extracellular or intracellular
CC osmotic changes (PubMed:24725410, PubMed:29769723, PubMed:24790029,
CC PubMed:26530471, PubMed:26824658, PubMed:28193731). The VRAC channel
CC conducts iodide better than chloride and can also conduct organic
CC osmolytes like taurine (PubMed:24725410, PubMed:30095067,
CC PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731).
CC Mediates efflux of amino acids, such as aspartate and glutamate, in
CC response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are
CC required for the uptake of the drug cisplatin (PubMed:26530471). In
CC complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive
CC cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced
CC in response to DNA virus in the cytosol: mediates both import and
CC export of 2'-3'-cGAMP, thereby promoting transfer of 2'-3'-cGAMP to
CC bystander cells (PubMed:33171122). In contrast, complexes containing
CC LRRC8D inhibit transport of 2'-3'-cGAMP (PubMed:33171122). Required for
CC in vivo channel activity, together with at least one other family
CC member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics
CC depend on the precise subunit composition (PubMed:24790029,
CC PubMed:26824658, PubMed:28193731). Can form functional channels by
CC itself (in vitro) (PubMed:26824658). Involved in B-cell development:
CC required for the pro-B cell to pre-B cell transition (PubMed:14660746).
CC Also required for T-cell development (By similarity). Required for
CC myoblast differentiation: VRAC activity promotes membrane
CC hyperpolarization and regulates insulin-stimulated glucose metabolism
CC and oxygen consumption (By similarity). Also acts as a regulator of
CC glucose-sensing in pancreatic beta cells: VRAC currents, generated in
CC response to hypotonicity- or glucose-induced beta cell swelling,
CC depolarize cells, thereby causing electrical excitation, leading to
CC increase glucose sensitivity and insulin secretion (PubMed:29371604).
CC Also plays a role in lysosome homeostasis by forming functional
CC lysosomal VRAC channels in response to low cytoplasmic ionic strength
CC condition: lysosomal VRAC channels are necessary for the formation of
CC large lysosome-derived vacuoles, which store and then expel excess
CC water to maintain cytosolic water homeostasis (PubMed:31270356,
CC PubMed:33139539). {ECO:0000250|UniProtKB:Q80WG5,
CC ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26530471,
CC ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731,
CC ECO:0000269|PubMed:29371604, ECO:0000269|PubMed:29769723,
CC ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:31270356,
CC ECO:0000269|PubMed:33139539, ECO:0000269|PubMed:33171122}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC ChEBI:CHEBI:17996; Evidence={ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24790029};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=iodide(out) = iodide(in); Xref=Rhea:RHEA:66324,
CC ChEBI:CHEBI:16382; Evidence={ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24790029};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=taurine(out) = taurine(in); Xref=Rhea:RHEA:66328,
CC ChEBI:CHEBI:507393; Evidence={ECO:0000269|PubMed:24790029};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate(out) = L-aspartate(in); Xref=Rhea:RHEA:66332,
CC ChEBI:CHEBI:29991; Evidence={ECO:0000250|UniProtKB:Q4V8I7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutamate(out) = L-glutamate(in); Xref=Rhea:RHEA:66336,
CC ChEBI:CHEBI:29985; Evidence={ECO:0000305|PubMed:28193731};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=myo-inositol(out) = myo-inositol(in); Xref=Rhea:RHEA:32867,
CC ChEBI:CHEBI:17268; Evidence={ECO:0000250|UniProtKB:Q4V8I7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2',3'-cGAMP(out) = 2',3'-cGAMP(in); Xref=Rhea:RHEA:66320,
CC ChEBI:CHEBI:143093; Evidence={ECO:0000269|PubMed:33171122};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66321;
CC Evidence={ECO:0000269|PubMed:33171122};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:66322;
CC Evidence={ECO:0000269|PubMed:33171122};
CC -!- ACTIVITY REGULATION: Inhibited by (4-[(2-butyl-6,7-dichloro-2-
CC cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which
CC plugs the channel like a cork in a bottle by binding in the
CC extracellular selectivity filter and sterically occluding ion
CC conduction. {ECO:0000250|UniProtKB:Q80WG5}.
CC -!- SUBUNIT: Hexamer; forms a trimer of dimers (PubMed:30095067,
CC PubMed:30127360). Heterohexamer; oligomerizes with other LRRC8 proteins
CC (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer
CC (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:30095067).
CC Can form homohexamers in vitro, but these have lower conductance than
CC heterohexamers (PubMed:26824658). Detected in a channel complex that
CC contains LRRC8A, LRRC8C and LRRC8E (PubMed:28193731). In vivo, the
CC subunit composition may depend primarily on expression levels, and
CC heterooligomeric channels containing various proportions of the
CC different LRRC8 proteins may coexist (Probable). Interact with GRB2 (By
CC similarity). {ECO:0000250|UniProtKB:Q80WG5,
CC ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029,
CC ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731,
CC ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:30127360, ECO:0000305}.
CC -!- INTERACTION:
CC Q8IWT6; Q8IWT6: LRRC8A; NbExp=3; IntAct=EBI-10970086, EBI-10970086;
CC Q8IWT6; Q6P9F7: LRRC8B; NbExp=3; IntAct=EBI-10970086, EBI-9477617;
CC Q8IWT6; Q8TDW0: LRRC8C; NbExp=2; IntAct=EBI-10970086, EBI-6916516;
CC Q8IWT6; Q7L1W4: LRRC8D; NbExp=2; IntAct=EBI-10970086, EBI-861997;
CC Q8IWT6; Q6NSJ5: LRRC8E; NbExp=3; IntAct=EBI-10970086, EBI-8647013;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029,
CC ECO:0000269|PubMed:26824658, ECO:0000305|PubMed:29769723}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029,
CC ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:30127360}. Lysosome
CC membrane {ECO:0000269|PubMed:33139539}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24782309,
CC ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:30095067,
CC ECO:0000269|PubMed:30127360}. Note=Mainly localizes to the cell
CC membrane, with some intracellular localization to lysosomes.
CC {ECO:0000269|PubMed:33139539}.
CC -!- TISSUE SPECIFICITY: Expressed in brain, kidney, ovary, lung, liver,
CC heart, and fetal brain and liver. Found at high levels in bone marrow;
CC lower levels are detected in peripheral blood cells. Expressed on T-
CC cells as well as on B-lineage cells. {ECO:0000269|PubMed:10718198,
CC ECO:0000269|PubMed:14660746}.
CC -!- DOMAIN: The volume-regulated anion channel (VRAC) channel forms a
CC trimer of dimers, with symmetry mismatch between the pore-forming
CC domain and the cytosolic LRR repeats, a topology similar to gap
CC junction proteins. {ECO:0000269|PubMed:30095067,
CC ECO:0000269|PubMed:30127360}.
CC -!- DOMAIN: The di-leucine motif is required for lysosomal localization.
CC {ECO:0000269|PubMed:33139539}.
CC -!- DOMAIN: The cytoplasmic N-terminus preceding the first transmembrane
CC (residues 1-22) regulates volume-regulated anion channel (VRAC)
CC conductance, ion permeability and inactivation gating.
CC {ECO:0000269|PubMed:29925591}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:24790029}.
CC -!- DISEASE: Agammaglobulinemia 5, autosomal dominant (AGM5) [MIM:613506]:
CC A primary immunodeficiency characterized by profoundly low or absent
CC serum antibodies and low or absent circulating B-cells due to an early
CC block of B-cell development. Affected individuals develop severe
CC infections in the first years of life. {ECO:0000269|PubMed:14660746}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry. A chromosomal aberration involving LRRC8 has been found
CC in a patient with congenital agammaglobulinemia. Translocation
CC t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene,
CC resulting in deletion of the eighth, ninth, and half of the seventh LRR
CC domains.
CC -!- SIMILARITY: Belongs to the LRRC8 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ88653.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAA92675.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC11161.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=LRRC8Abase; Note=LRRC8A mutation db;
CC URL="http://structure.bmc.lu.se/idbase/LRRC8Abase/";
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DR EMBL; AY143166; AAN18279.1; -; mRNA.
DR EMBL; AB037858; BAA92675.1; ALT_INIT; mRNA.
DR EMBL; AL672142; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC051322; AAH51322.1; -; mRNA.
DR EMBL; AY358286; AAQ88653.1; ALT_INIT; mRNA.
DR EMBL; AK074723; BAC11161.1; ALT_INIT; mRNA.
DR CCDS; CCDS35155.1; -.
DR RefSeq; NP_001120716.1; NM_001127244.1.
DR RefSeq; NP_001120717.1; NM_001127245.1.
DR RefSeq; NP_062540.2; NM_019594.3.
DR RefSeq; XP_005252152.1; XM_005252095.2.
DR RefSeq; XP_005252153.1; XM_005252096.3.
DR RefSeq; XP_006717249.1; XM_006717186.2.
DR RefSeq; XP_011517165.1; XM_011518863.1.
DR RefSeq; XP_011517166.1; XM_011518864.2.
DR RefSeq; XP_011517167.1; XM_011518865.2.
DR PDB; 5ZSU; EM; 4.25 A; A/B/C/D/E/F=1-810.
DR PDB; 6DJB; EM; 4.40 A; A/B/C/D/E/F=1-810.
DR PDBsum; 5ZSU; -.
DR PDBsum; 6DJB; -.
DR AlphaFoldDB; Q8IWT6; -.
DR SMR; Q8IWT6; -.
DR BioGRID; 121126; 88.
DR CORUM; Q8IWT6; -.
DR DIP; DIP-61360N; -.
DR IntAct; Q8IWT6; 27.
DR MINT; Q8IWT6; -.
DR STRING; 9606.ENSP00000259324; -.
DR TCDB; 1.A.25.3.1; the gap junction-forming innexin (innexin) family.
DR GlyGen; Q8IWT6; 3 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q8IWT6; -.
DR PhosphoSitePlus; Q8IWT6; -.
DR BioMuta; LRRC8A; -.
DR DMDM; 37537912; -.
DR EPD; Q8IWT6; -.
DR jPOST; Q8IWT6; -.
DR MassIVE; Q8IWT6; -.
DR MaxQB; Q8IWT6; -.
DR PaxDb; Q8IWT6; -.
DR PeptideAtlas; Q8IWT6; -.
DR PRIDE; Q8IWT6; -.
DR ProteomicsDB; 70893; -.
DR Antibodypedia; 17736; 170 antibodies from 22 providers.
DR DNASU; 56262; -.
DR Ensembl; ENST00000259324.5; ENSP00000259324.5; ENSG00000136802.12.
DR Ensembl; ENST00000372599.7; ENSP00000361680.3; ENSG00000136802.12.
DR Ensembl; ENST00000372600.9; ENSP00000361682.4; ENSG00000136802.12.
DR GeneID; 56262; -.
DR KEGG; hsa:56262; -.
DR MANE-Select; ENST00000372600.9; ENSP00000361682.4; NM_019594.4; NP_062540.2.
DR UCSC; uc004bwl.5; human.
DR CTD; 56262; -.
DR DisGeNET; 56262; -.
DR GeneCards; LRRC8A; -.
DR HGNC; HGNC:19027; LRRC8A.
DR HPA; ENSG00000136802; Low tissue specificity.
DR MalaCards; LRRC8A; -.
DR MIM; 608360; gene.
DR MIM; 613506; phenotype.
DR neXtProt; NX_Q8IWT6; -.
DR OpenTargets; ENSG00000136802; -.
DR Orphanet; 33110; Autosomal agammaglobulinemia.
DR PharmGKB; PA134909315; -.
DR VEuPathDB; HostDB:ENSG00000136802; -.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000154043; -.
DR HOGENOM; CLU_019019_0_0_1; -.
DR InParanoid; Q8IWT6; -.
DR OMA; PMLQRSK; -.
DR OrthoDB; 158390at2759; -.
DR PhylomeDB; Q8IWT6; -.
DR TreeFam; TF331443; -.
DR PathwayCommons; Q8IWT6; -.
DR Reactome; R-HSA-5223345; Miscellaneous transport and binding events.
DR SignaLink; Q8IWT6; -.
DR BioGRID-ORCS; 56262; 22 hits in 1087 CRISPR screens.
DR ChiTaRS; LRRC8A; human.
DR GeneWiki; LRRC8A; -.
DR GenomeRNAi; 56262; -.
DR Pharos; Q8IWT6; Tbio.
DR PRO; PR:Q8IWT6; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q8IWT6; protein.
DR Bgee; ENSG00000136802; Expressed in gingival epithelium and 187 other tissues.
DR ExpressionAtlas; Q8IWT6; baseline and differential.
DR Genevisible; Q8IWT6; HS.
DR GO; GO:0009986; C:cell surface; IDA:MGI.
DR GO; GO:1905103; C:integral component of lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0034702; C:ion channel complex; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0140360; F:cyclic-GMP-AMP transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005225; F:volume-sensitive anion channel activity; IDA:UniProtKB.
DR GO; GO:0098656; P:anion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006820; P:anion transport; IMP:UniProtKB.
DR GO; GO:0015810; P:aspartate transmembrane transport; IEA:Ensembl.
DR GO; GO:0006884; P:cell volume homeostasis; IDA:UniProtKB.
DR GO; GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
DR GO; GO:1902476; P:chloride transmembrane transport; IDA:UniProtKB.
DR GO; GO:0140361; P:cyclic-GMP-AMP transmembrane import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; ISS:UniProtKB.
DR GO; GO:0002329; P:pre-B cell differentiation; ISS:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB.
DR GO; GO:0006970; P:response to osmotic stress; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0015734; P:taurine transport; IEA:Ensembl.
DR Gene3D; 3.80.10.10; -; 2.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR021040; LRRC8_Pannexin-like.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF12534; Pannexin_like; 1.
DR SMART; SM00369; LRR_TYP; 8.
DR PROSITE; PS51450; LRR; 11.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Chromosomal rearrangement;
KW Differentiation; Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Ion channel; Ion transport; Leucine-rich repeat; Lysosome; Membrane;
KW Phosphoprotein; Reference proteome; Repeat; Spermatogenesis; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..810
FT /note="Volume-regulated anion channel subunit LRRC8A"
FT /id="PRO_0000084499"
FT TOPO_DOM 1..23
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 24..47
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30095067,
FT ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT TOPO_DOM 48..123
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 124..142
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30095067,
FT ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT TOPO_DOM 143..264
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 265..286
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30095067,
FT ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT TOPO_DOM 287..316
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 317..341
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30095067,
FT ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT TOPO_DOM 342..810
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:24782309"
FT REPEAT 399..422
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 423..445
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 447..468
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT REPEAT 469..492
FT /note="LRR 4"
FT /evidence="ECO:0000255"
FT REPEAT 493..515
FT /note="LRR 5"
FT /evidence="ECO:0000255"
FT REPEAT 518..542
FT /note="LRR 6"
FT /evidence="ECO:0000255"
FT REPEAT 543..565
FT /note="LRR 7"
FT /evidence="ECO:0000255"
FT REPEAT 567..589
FT /note="LRR 8"
FT /evidence="ECO:0000255"
FT REPEAT 590..613
FT /note="LRR 9"
FT /evidence="ECO:0000255"
FT REPEAT 615..637
FT /note="LRR 10"
FT /evidence="ECO:0000255"
FT REPEAT 639..661
FT /note="LRR 11"
FT /evidence="ECO:0000255"
FT REPEAT 662..684
FT /note="LRR 12"
FT /evidence="ECO:0000255"
FT REPEAT 686..707
FT /note="LRR 13"
FT /evidence="ECO:0000255"
FT REPEAT 708..730
FT /note="LRR 14"
FT /evidence="ECO:0000255"
FT REPEAT 732..753
FT /note="LRR 15"
FT /evidence="ECO:0000255"
FT REPEAT 754..776
FT /note="LRR 16"
FT /evidence="ECO:0000255"
FT REPEAT 778..801
FT /note="LRR 17"
FT /evidence="ECO:0000255"
FT MOTIF 706..707
FT /note="Di-leucine motif"
FT /evidence="ECO:0000269|PubMed:33139539"
FT SITE 103
FT /note="Required for anion selectivity"
FT /evidence="ECO:0000269|PubMed:30095067"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PubMed:22814378"
FT MOD_RES 200
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT MOD_RES 202
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT MOD_RES 215
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 217
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT CARBOHYD 66
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 83
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..310
FT /evidence="ECO:0000269|PubMed:30095067,
FT ECO:0000269|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT DISULFID 57..65
FT /evidence="ECO:0000269|PubMed:30095067,
FT ECO:0007744|PDB:6DJB"
FT DISULFID 113..295
FT /evidence="ECO:0000269|PubMed:30095067,
FT ECO:0000269|PubMed:30127360, ECO:0007744|PDB:5ZSU,
FT ECO:0007744|PDB:6DJB"
FT VARIANT 545
FT /note="R -> H (found in a patient with Sertoli cell-only
FT syndrome; unknown pathological significance;
FT dbSNP:rs769167142)"
FT /evidence="ECO:0000269|PubMed:30135305"
FT /id="VAR_084194"
FT MUTAGEN 5
FT /note="T->C: No effect."
FT /evidence="ECO:0000269|PubMed:30095067"
FT MUTAGEN 5
FT /note="T->R: Anion channel is more selective to iodite
FT compared to chloride."
FT /evidence="ECO:0000269|PubMed:30095067"
FT MUTAGEN 6
FT /note="E->C: Decreased amplitudes of swelling-activated
FT currents."
FT /evidence="ECO:0000269|PubMed:29925591"
FT MUTAGEN 44
FT /note="T->A,C: Altered anion selectivity."
FT /evidence="ECO:0000269|PubMed:24725410"
FT MUTAGEN 66
FT /note="N->A: Abolishes N-glycosylation; when associated
FT with A-83."
FT /evidence="ECO:0000269|PubMed:24790029"
FT MUTAGEN 83
FT /note="N->A: Abolishes N-glycosylation; when associated
FT with A-66."
FT /evidence="ECO:0000269|PubMed:24790029"
FT MUTAGEN 103
FT /note="R->F: Affects ion selectivity of the channel."
FT /evidence="ECO:0000269|PubMed:30095067"
FT MUTAGEN 103
FT /note="R->L: Abolished ability to transport 2'-3'-cGAMP."
FT /evidence="ECO:0000269|PubMed:33171122"
FT MUTAGEN 706..707
FT /note="LL->AA: Abolished localization to lysosomes."
FT /evidence="ECO:0000269|PubMed:33139539"
FT CONFLICT 323
FT /note="S -> P (in Ref. 7; BAC11161)"
FT /evidence="ECO:0000305"
FT CONFLICT 744
FT /note="Q -> R (in Ref. 7; BAC11161)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 810 AA; 94199 MW; E0C5E6EBEE8275E8 CRC64;
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV
TKDSCNDSFR GWAAPGPEPT YPNSTILPTP DTGPTGIKYD LDRHQYNYVD AVCYENRLHW
FAKYFPYLVL LHTLIFLACS NFWFKFPRTS SKLEHFVSIL LKCFDSPWTT RALSETVVEE
SDPKPAFSKM NGSMDKKSST VSEDVEATVP MLQRTKSRIE QGIVDRSETG VLDKKEGEQA
KALFEKVKKF RTHVEEGDIV YRLYMRQTII KVIKFILIIC YTVYYVHNIK FDVDCTVDIE
SLTGYRTYRC AHPLATLFKI LASFYISLVI FYGLICMYTL WWMLRRSLKK YSFESIREES
SYSDIPDVKN DFAFMLHLID QYDPLYSKRF AVFLSEVSEN KLRQLNLNNE WTLDKLRQRL
TKNAQDKLEL HLFMLSGIPD TVFDLVELEV LKLELIPDVT IPPSIAQLTG LKELWLYHTA
AKIEAPALAF LRENLRALHI KFTDIKEIPL WIYSLKTLEE LHLTGNLSAE NNRYIVIDGL
RELKRLKVLR LKSNLSKLPQ VVTDVGVHLQ KLSINNEGTK LIVLNSLKKM ANLTELELIR
CDLERIPHSI FSLHNLQEID LKDNNLKTIE EIISFQHLHR LTCLKLWYNH IAYIPIQIGN
LTNLERLYLN RNKIEKIPTQ LFYCRKLRYL DLSHNNLTFL PADIGLLQNL QNLAITANRI
ETLPPELFQC RKLRALHLGN NVLQSLPSRV GELTNLTQIE LRGNRLECLP VELGECPLLK
RSGLVVEEDL FNTLPPEVKE RLWRADKEQA
