GUC2D_HUMAN
ID GUC2D_HUMAN Reviewed; 1103 AA.
AC Q02846; Q6LEA7;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 2.
DT 03-AUG-2022, entry version 224.
DE RecName: Full=Retinal guanylyl cyclase 1;
DE Short=RETGC-1;
DE EC=4.6.1.2 {ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830, ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355, ECO:0000269|PubMed:7912093, ECO:0000269|PubMed:9600905};
DE AltName: Full=CG-E {ECO:0000303|PubMed:30319355};
DE AltName: Full=Guanylate cyclase 2D, retinal;
DE AltName: Full=Rod outer segment membrane guanylate cyclase;
DE Short=ROS-GC;
DE Flags: Precursor;
GN Name=GUCY2D;
GN Synonyms=CORD6, GUC1A4, GUC2D {ECO:0000303|PubMed:7806240}, RETGC, RETGC1;
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].
RC TISSUE=Retina;
RX PubMed=1356371; DOI=10.1016/0896-6273(92)90035-c;
RA Shyjan A.W., de Sauvage F.J., Gillett N.A., Goeddel D.V., Lowe D.G.;
RT "Molecular cloning of a retina-specific membrane guanylyl cyclase.";
RL Neuron 9:727-737(1992).
RN [2]
RP SEQUENCE REVISION.
RA Lowe D.G.;
RL Submitted (JAN-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Perrault I.;
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1009-1088.
RX PubMed=7806240; DOI=10.1006/geno.1994.1415;
RA Oliveira L., Miniou P., Viegas-Pequignot E., Rozet J.-M., Dollfus H.,
RA Pittler S.J.;
RT "Human retinal guanylate cyclase (GUC2D) maps to chromosome 17p13.1.";
RL Genomics 22:478-481(1994).
RN [5]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY.
RX PubMed=7912093; DOI=10.1016/0896-6273(94)90449-9;
RA Dizhoor A.M., Lowe D.G., Olshevskaya E.V., Laura R.P., Hurley J.B.;
RT "The human photoreceptor membrane guanylyl cyclase, RetGC, is present in
RT outer segments and is regulated by calcium and a soluble activator.";
RL Neuron 12:1345-1352(1994).
RN [6]
RP MUTAGENESIS OF GLU-925 AND CYS-997, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=9600905; DOI=10.1073/pnas.95.11.5993;
RA Tucker C.L., Hurley J.H., Miller T.R., Hurley J.B.;
RT "Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an
RT adenylyl cyclase.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:5993-5997(1998).
RN [7]
RP 3D-STRUCTURE MODELING OF 871-1028.
RX PubMed=9391039; DOI=10.1073/pnas.94.25.13414;
RA Liu Y., Ruoho A.E., Rao V.D., Hurley J.H.;
RT "Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and
RT mutational analysis.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:13414-13419(1997).
RN [8]
RP VARIANT LCA1 SER-52.
RX PubMed=8944027; DOI=10.1038/ng1296-461;
RA Perrault I., Rozet J.-M., Calvas P., Gerber S., Camuzat A., Dollfus H.,
RA Chatelin S., Souied E., Ghazi I., Leowski C., Bonnemaison M.,
RA le Paslier D., Frezal J., Dufier J.-L., Pittler S., Munnich A., Kaplan J.;
RT "Retinal-specific guanylate cyclase gene mutations in Leber's congenital
RT amaurosis.";
RL Nat. Genet. 14:461-464(1996).
RN [9]
RP VARIANT CORD6 837-ASP--MET-839.
RX PubMed=9683616; DOI=10.1086/301985;
RA Perrault I., Rozet J.-M., Gerber S., Kelsell R.E., Souied E., Cabot A.,
RA Hunt D.M., Munnich A., Kaplan J.;
RT "A retGC-1 mutation in autosomal dominant cone-rod dystrophy.";
RL Am. J. Hum. Genet. 63:651-654(1998).
RN [10]
RP VARIANTS CORD6 ASP-837 AND CYS-838.
RX PubMed=9618177; DOI=10.1093/hmg/7.7.1179;
RA Kelsell R.E., Gregory-Evans K., Payne A.M., Perrault I., Kaplan J.,
RA Yang R.-B., Garbers D.L., Bird A.C., Moore A.T., Hunt D.M.;
RT "Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant
RT cone-rod dystrophy.";
RL Hum. Mol. Genet. 7:1179-1184(1998).
RN [11]
RP CHARACTERIZATION OF VARIANT LCA1 SER-565.
RX PubMed=9888789; DOI=10.1021/bi9824137;
RA Duda T., Venkataraman V., Goraczniak R., Lange C., Koch K.-W., Sharma R.K.;
RT "Functional consequences of a rod outer segment membrane guanylate cyclase
RT (ROS-GC1) gene mutation linked with Leber's congenital amaurosis.";
RL Biochemistry 38:509-515(1999).
RN [12]
RP VARIANTS LCA1 TYR-105; PRO-325 AND SER-858.
RX PubMed=11035546; DOI=10.1076/1381-6810(200009)2131-zft135;
RA Dharmaraj S.R., Silva E.R., Pina A.-L., Li Y.Y., Yang J.M., Carter C.R.,
RA Loyer M.K., El-Hilali H.K., Traboulsi E.K., Sundin O.K., Zhu D.K.,
RA Koenekoop R.K., Maumenee I.H.;
RT "Mutational analysis and clinical correlation in Leber congenital
RT amaurosis.";
RL Ophthalmic Genet. 21:135-150(2000).
RN [13]
RP VARIANT LCA1 PRO-954.
RX PubMed=12365911; DOI=10.1001/archopht.120.10.1325;
RA Koenekoop R.K., Fishman G.A., Iannaccone A., Ezzeldin H., Ciccarelli M.L.,
RA Baldi A., Sunness J.S., Lotery A.J., Jablonski M.M., Pittler S.J.,
RA Maumenee I.;
RT "Electroretinographic abnormalities in parents of patients with Leber
RT congenital amaurosis who have heterozygous GUCY2D mutations.";
RL Arch. Ophthalmol. 120:1325-1330(2002).
RN [14]
RP VARIANTS CORD6 CYS-838 AND HIS-838, AND DISCUSSION OF PHENOTYPIC
RP VARIABILITY.
RX PubMed=12552567; DOI=10.1002/humu.9109;
RA Udar N., Yelchits S., Chalukya M., Yellore V., Nusinowitz S.,
RA Silva-Garcia R., Vrabec T., Hussles Maumenee I., Donoso L., Small K.W.;
RT "Identification of GUCY2D gene mutations in CORD5 families and evidence of
RT incomplete penetrance.";
RL Hum. Mutat. 21:170-171(2003).
RN [15]
RP INVOLVEMENT IN CORD6.
RX PubMed=15111605; DOI=10.1167/iovs.03-0315;
RA Ito S., Nakamura M., Nuno Y., Ohnishi Y., Nishida T., Miyake Y.;
RT "Novel complex GUCY2D mutation in Japanese family with cone-rod
RT dystrophy.";
RL Invest. Ophthalmol. Vis. Sci. 45:1480-1485(2004).
RN [16]
RP CHARACTERIZATION OF VARIANTS LCA1 TYR-105; PRO-325; SER-858 AND PRO-954,
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=15123990;
RA Tucker C.L., Ramamurthy V., Pina A.-L., Loyer M., Dharmaraj S., Li Y.,
RA Maumenee I.H., Hurley J.B., Koenekoop R.K.;
RT "Functional analyses of mutant recessive GUCY2D alleles identified in Leber
RT congenital amaurosis patients: protein domain comparisons and dominant
RT negative effects.";
RL Mol. Vis. 10:297-303(2004).
RN [17]
RP POSSIBLE INVOLVEMENT OF VARIANT SER-701 IN LEBER CONGENITAL AMAUROSIS.
RX PubMed=16123401; DOI=10.1167/iovs.05-0111;
RA Zernant J., Kulm M., Dharmaraj S., den Hollander A.I., Perrault I.,
RA Preising M.N., Lorenz B., Kaplan J., Cremers F.P., Maumenee I.,
RA Koenekoop R.K., Allikmets R.;
RT "Genotyping microarray (disease chip) for Leber congenital amaurosis:
RT detection of modifier alleles.";
RL Invest. Ophthalmol. Vis. Sci. 46:3052-3059(2005).
RN [18]
RP VARIANTS LCA1 TRP-768 AND GLN-795, VARIANTS ARG-325 AND SER-701, AND
RP POSSIBLE INVOLVEMENT OF VARIANT SER-701 IN LEBER CONGENITAL AMAUROSIS.
RX PubMed=17724218; DOI=10.1167/iovs.07-0068;
RA Simonelli F., Ziviello C., Testa F., Rossi S., Fazzi E., Bianchi P.E.,
RA Fossarello M., Signorini S., Bertone C., Galantuomo S., Brancati F.,
RA Valente E.M., Ciccodicola A., Rinaldi E., Auricchio A., Banfi S.;
RT "Clinical and molecular genetics of Leber's congenital amaurosis: a
RT multicenter study of Italian patients.";
RL Invest. Ophthalmol. Vis. Sci. 48:4284-4290(2007).
RN [19]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-328; ASP-431; MET-507; GLU-693; SER-701
RP AND HIS-782.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [20]
RP INVOLVEMENT IN CORD6.
RX PubMed=18332321; DOI=10.1001/archopht.126.3.397;
RA Small K.W., Silva-Garcia R., Udar N., Nguyen E.V., Heckenlively J.R.;
RT "New mutation, P575L, in the GUCY2D gene in a family with autosomal
RT dominant progressive cone degeneration.";
RL Arch. Ophthalmol. 126:397-403(2008).
RN [21]
RP INVOLVEMENT IN CORD6, AND VARIANTS CORD6 CYS-838; HIS-838 AND GLY-838.
RX PubMed=18487367; DOI=10.1167/iovs.08-1901;
RA Kitiratschky V.B., Wilke R., Renner A.B., Kellner U., Vadala M.,
RA Birch D.G., Wissinger B., Zrenner E., Kohl S.;
RT "Mutation analysis identifies GUCY2D as the major gene responsible for
RT autosomal dominant progressive cone degeneration.";
RL Invest. Ophthalmol. Vis. Sci. 49:5015-5023(2008).
RN [22]
RP INVOLVEMENT IN CORD6, AND VARIANT CORD6 THR-949.
RX PubMed=20517349; DOI=10.1038/ejhg.2010.81;
RA Ugur Iseri S.A., Durlu Y.K., Tolun A.;
RT "A novel recessive GUCY2D mutation causing cone-rod dystrophy and not
RT Leber's congenital amaurosis.";
RL Eur. J. Hum. Genet. 18:1121-1126(2010).
RN [23]
RP INTERACTION WITH RD3.
RX PubMed=21078983; DOI=10.1073/pnas.1010460107;
RA Azadi S., Molday L.L., Molday R.S.;
RT "RD3, the protein associated with Leber congenital amaurosis type 12, is
RT required for guanylate cyclase trafficking in photoreceptor cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:21158-21163(2010).
RN [24]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
RP INTERACTION WITH RD3, AND FUNCTION.
RX PubMed=21928830; DOI=10.1021/bi201342b;
RA Peshenko I.V., Olshevskaya E.V., Azadi S., Molday L.L., Molday R.S.,
RA Dizhoor A.M.;
RT "Retinal degeneration 3 (RD3) protein inhibits catalytic activity of
RT retinal membrane guanylyl cyclase (RetGC) and its stimulation by activating
RT proteins.";
RL Biochemistry 50:9511-9519(2011).
RN [25]
RP INVOLVEMENT IN CACD1, AND VARIANT CACD1 ALA-933.
RX PubMed=22695961; DOI=10.1167/iovs.12-10061;
RA Hughes A.E., Meng W., Lotery A.J., Bradley D.T.;
RT "A novel GUCY2D mutation, V933A, causes central areolar choroidal
RT dystrophy.";
RL Invest. Ophthalmol. Vis. Sci. 53:4748-4753(2012).
RN [26]
RP MUTAGENESIS OF ARG-822 AND MET-823, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=26100624; DOI=10.1074/jbc.m115.661371;
RA Peshenko I.V., Olshevskaya E.V., Dizhoor A.M.;
RT "Dimerization Domain of Retinal Membrane Guanylyl Cyclase 1 (RetGC1) Is an
RT Essential Part of Guanylyl Cyclase-activating Protein (GCAP) Binding
RT Interface.";
RL J. Biol. Chem. 290:19584-19596(2015).
RN [27]
RP CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, VARIANT LCA1 LEU-902,
RP CHARACTERIZATION OF VARIANT LCA1 VAL-710 AND LEU-902, VARIANT CORD6
RP ARG-873, AND CHARACTERIZATION OF VARIANTS CORD6 LYS-841; ASN-846 AND
RP ARG-873.
RX PubMed=30319355; DOI=10.3389/fnmol.2018.00348;
RA Wimberg H., Lev D., Yosovich K., Namburi P., Banin E., Sharon D.,
RA Koch K.W.;
RT "Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal
RT Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis.";
RL Front. Mol. Neurosci. 11:348-348(2018).
RN [28]
RP VARIANT CORD6 PRO-838.
RX PubMed=21552474;
RA Garcia-Hoyos M., Auz-Alexandre C.L., Almoguera B., Cantalapiedra D.,
RA Riveiro-Alvarez R., Lopez-Martinez M.A., Gimenez A., Blanco-Kelly F.,
RA Avila-Fernandez A., Trujillo-Tiebas M.J., Garcia-Sandoval B., Ramos C.,
RA Ayuso C.;
RT "Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish
RT families with autosomal dominant cone, cone-rod, and macular dystrophies.";
RL Mol. Vis. 17:1103-1109(2011).
RN [29]
RP VARIANT CORD6 HIS-838.
RX PubMed=22194653;
RA Xiao X., Guo X., Jia X., Li S., Wang P., Zhang Q.;
RT "A recurrent mutation in GUCY2D associated with autosomal dominant cone
RT dystrophy in a Chinese family.";
RL Mol. Vis. 17:3271-3278(2011).
RN [30]
RP VARIANTS LCA1 MET-55; VAL-103; MET-312; 405-PRO-ASN-406; CYS-438; LEU-640;
RP GLN-660; HIS-728; ALA-734; TRP-768; ARG-784 AND LEU-1007; GLY-ILE-1027 INS,
RP AND VARIANTS ARG-21; SER-52 AND SER-701.
RX PubMed=21602930; DOI=10.1371/journal.pone.0019458;
RA Li L., Xiao X., Li S., Jia X., Wang P., Guo X., Jiao X., Zhang Q.,
RA Hejtmancik J.F.;
RT "Detection of variants in 15 genes in 87 unrelated Chinese patients with
RT Leber congenital amaurosis.";
RL PLoS ONE 6:E19458-E19458(2011).
RN [31]
RP VARIANT CORD6 ALA-849.
RX PubMed=23734073;
RA Zhao X., Ren Y., Zhang X., Chen C., Dong B., Li Y.;
RT "A novel GUCY2D mutation in a Chinese family with dominant cone
RT dystrophy.";
RL Mol. Vis. 19:1039-1046(2013).
RN [32]
RP VARIANT CORD6 HIS-838.
RX PubMed=24480840; DOI=10.1038/eye.2014.7;
RA Mukherjee R., Robson A.G., Holder G.E., Stockman A., Egan C.A., Moore A.T.,
RA Webster A.R.;
RT "A detailed phenotypic description of autosomal dominant cone dystrophy due
RT to a de novo mutation in the GUCY2D gene.";
RL Eye 28:481-487(2014).
RN [33]
RP VARIANTS CORD6 CYS-838; LYS-841 AND ASN-846.
RX PubMed=25515582; DOI=10.1167/iovs.14-15647;
RA Lazar C.H., Mutsuddi M., Kimchi A., Zelinger L., Mizrahi-Meissonnier L.,
RA Marks-Ohana D., Boleda A., Ratnapriya R., Sharon D., Swaroop A., Banin E.;
RT "Whole exome sequencing reveals GUCY2D as a major gene associated with cone
RT and cone-rod dystrophy in Israel.";
RL Invest. Ophthalmol. Vis. Sci. 56:420-430(2014).
RN [34]
RP VARIANT LCA1 VAL-710.
RX PubMed=27475985; DOI=10.1186/s12881-016-0314-2;
RA Gradstein L., Zolotushko J., Sergeev Y.V., Lavy I., Narkis G., Perez Y.,
RA Guigui S., Sharon D., Banin E., Walter E., Lifshitz T., Birk O.S.;
RT "Novel GUCY2D mutation causes phenotypic variability of Leber congenital
RT amaurosis in a large kindred.";
RL BMC Med. Genet. 17:52-52(2016).
RN [35]
RP INVOLVEMENT IN CSNB1I, AND VARIANT CSNB1I TRP-768.
RX PubMed=29559409; DOI=10.1016/j.ajo.2018.03.021;
RA Stunkel M.L., Brodie S.E., Cideciyan A.V., Pfeifer W.L., Kennedy E.L.,
RA Stone E.M., Jacobson S.G., Drack A.V.;
RT "Expanded Retinal Disease Spectrum Associated With Autosomal Recessive
RT Mutations in GUCY2D.";
RL Am. J. Ophthalmol. 190:58-68(2018).
CC -!- FUNCTION: Catalyzes the synthesis of cyclic GMP (cGMP) in rods and
CC cones of photoreceptors. Plays an essential role in phototransduction,
CC by mediating cGMP replenishment (PubMed:21928830, PubMed:30319355,
CC PubMed:26100624, PubMed:9600905, PubMed:15123990). May also participate
CC in the trafficking of membrane-asociated proteins to the photoreceptor
CC outer segment membrane (By similarity). {ECO:0000250|UniProtKB:P52785,
CC ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830,
CC ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355,
CC ECO:0000269|PubMed:9600905}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP = 3',5'-cyclic GMP + diphosphate; Xref=Rhea:RHEA:13665,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, ChEBI:CHEBI:57746; EC=4.6.1.2;
CC Evidence={ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830,
CC ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355,
CC ECO:0000269|PubMed:7912093, ECO:0000269|PubMed:9600905};
CC -!- ACTIVITY REGULATION: Activated by GUCA1A when free calcium ions
CC concentration is low, and inhibited by GUCA1A when free calcium ions
CC concentration is high (By similarity). Negatively regulated by RD3;
CC inhibits the basal and GUCA1A-stimulated guanylate cyclase activity
CC (PubMed:21928830). {ECO:0000250|UniProtKB:P52785,
CC ECO:0000269|PubMed:21928830}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.31 mM for GTP (in absence of RD3) {ECO:0000269|PubMed:21928830};
CC KM=1.57 mM for GTP (in presence of 30 nM of RD3)
CC {ECO:0000269|PubMed:21928830};
CC KM=0.94 mM for GTP (in presence of 60 nM of RD3)
CC {ECO:0000269|PubMed:21928830};
CC Vmax=3.5 nmol/min/mg enzyme (in absence of RD3)
CC {ECO:0000269|PubMed:21928830};
CC Vmax=1.4 nmol/min/mg enzyme (in presence of 30 nM of RD3)
CC {ECO:0000269|PubMed:21928830};
CC Vmax=0.7 nmol/min/mg enzyme (in presence of 60 nM of RD3)
CC {ECO:0000269|PubMed:21928830};
CC -!- SUBUNIT: Homodimer; requires homodimerization for guanylyl cyclase
CC activity (By similarity). Interacts with RD3; promotes the exit of
CC GUCY2D from the endoplasmic reticulum and its trafficking to the
CC photoreceptor outer segments (PubMed:21928830, PubMed:21078983).
CC Interaction with RD3 negatively regulates guanylate cyclase activity
CC (PubMed:21928830). {ECO:0000250|UniProtKB:P51840,
CC ECO:0000269|PubMed:21078983, ECO:0000269|PubMed:21928830}.
CC -!- INTERACTION:
CC Q02846; Q7Z3Z2: RD3; NbExp=3; IntAct=EBI-1756902, EBI-10257497;
CC -!- SUBCELLULAR LOCATION: Photoreceptor outer segment membrane
CC {ECO:0000269|PubMed:7912093}; Single-pass type I membrane protein
CC {ECO:0000255}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:30319355}; Single-pass type I membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Retina. {ECO:0000269|PubMed:7912093}.
CC -!- DISEASE: Leber congenital amaurosis 1 (LCA1) [MIM:204000]: A severe
CC dystrophy of the retina, typically becoming evident in the first years
CC of life. Visual function is usually poor and often accompanied by
CC nystagmus, sluggish or near-absent pupillary responses, photophobia,
CC high hyperopia and keratoconus. {ECO:0000269|PubMed:11035546,
CC ECO:0000269|PubMed:12365911, ECO:0000269|PubMed:15123990,
CC ECO:0000269|PubMed:17724218, ECO:0000269|PubMed:21602930,
CC ECO:0000269|PubMed:27475985, ECO:0000269|PubMed:30319355,
CC ECO:0000269|PubMed:8944027, ECO:0000269|PubMed:9888789}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Cone-rod dystrophy 6 (CORD6) [MIM:601777]: An inherited
CC retinal dystrophy characterized by retinal pigment deposits visible on
CC fundus examination, predominantly in the macular region, and initial
CC loss of cone photoreceptors followed by rod degeneration. This leads to
CC decreased visual acuity and sensitivity in the central visual field,
CC followed by loss of peripheral vision. Severe loss of vision occurs
CC earlier than in retinitis pigmentosa, due to cone photoreceptors
CC degenerating at a higher rate than rod photoreceptors.
CC {ECO:0000269|PubMed:12552567, ECO:0000269|PubMed:15111605,
CC ECO:0000269|PubMed:18332321, ECO:0000269|PubMed:18487367,
CC ECO:0000269|PubMed:20517349, ECO:0000269|PubMed:21552474,
CC ECO:0000269|PubMed:22194653, ECO:0000269|PubMed:23734073,
CC ECO:0000269|PubMed:24480840, ECO:0000269|PubMed:25515582,
CC ECO:0000269|PubMed:27475985, ECO:0000269|PubMed:30319355,
CC ECO:0000269|PubMed:9618177, ECO:0000269|PubMed:9683616}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Choroidal dystrophy, central areolar, 1 (CACD1) [MIM:215500]:
CC A form of central areolar choroidal dystrophy, a retinal disease that
CC affects the macula and results in a well-demarcated circumscribed area
CC of atrophy of the pigment epithelium and choriocapillaris. CACD1
CC inheritance is autosomal recessive. {ECO:0000269|PubMed:22695961}.
CC Note=The disease may be caused by variants affecting the gene
CC represented in this entry.
CC -!- DISEASE: Night blindness, congenital stationary, 1I (CSNB1I)
CC [MIM:618555]: A form of congenital stationary night blindness, a non-
CC progressive retinal disorder characterized by impaired night vision or
CC in dim light, with good vision only on bright days. CSNB1I patients
CC present with night blindness from infancy or early childhood. Visual
CC acuity is preserved, but some patients have color vision and/or visual
CC field defects. Progression to mild retinitis pigmentosa may occur.
CC CSNB1I inheritance is autosomal recessive.
CC {ECO:0000269|PubMed:29559409}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The gene names for receptor guanylyl cyclases are
CC inconsistent between mouse and human. The ortholog of the mouse Gucy2d
CC gene is a pseudogene in humans. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
CC -!- WEB RESOURCE: Name=Mutations of the GUCY2D gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="https://www.retina-international.org/files/sci-news/gcmut.htm";
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DR EMBL; M92432; AAA60547.1; -; mRNA.
DR EMBL; AJ222657; CAA10914.1; -; Genomic_DNA.
DR EMBL; L26921; AAA60366.1; -; Genomic_DNA.
DR CCDS; CCDS11127.1; -.
DR PIR; JH0717; JH0717.
DR RefSeq; NP_000171.1; NM_000180.3.
DR RefSeq; XP_011522118.1; XM_011523816.1.
DR AlphaFoldDB; Q02846; -.
DR SMR; Q02846; -.
DR BioGRID; 109255; 17.
DR IntAct; Q02846; 3.
DR STRING; 9606.ENSP00000254854; -.
DR TCDB; 8.A.85.1.3; the guanylate cyclase (gc) family.
DR GlyGen; Q02846; 1 site.
DR iPTMnet; Q02846; -.
DR PhosphoSitePlus; Q02846; -.
DR BioMuta; GUCY2D; -.
DR DMDM; 1345920; -.
DR jPOST; Q02846; -.
DR MassIVE; Q02846; -.
DR MaxQB; Q02846; -.
DR PaxDb; Q02846; -.
DR PeptideAtlas; Q02846; -.
DR PRIDE; Q02846; -.
DR ProteomicsDB; 58131; -.
DR Antibodypedia; 12365; 266 antibodies from 29 providers.
DR DNASU; 3000; -.
DR Ensembl; ENST00000254854.5; ENSP00000254854.4; ENSG00000132518.7.
DR GeneID; 3000; -.
DR KEGG; hsa:3000; -.
DR MANE-Select; ENST00000254854.5; ENSP00000254854.4; NM_000180.4; NP_000171.1.
DR UCSC; uc002gjt.3; human.
DR CTD; 3000; -.
DR DisGeNET; 3000; -.
DR GeneCards; GUCY2D; -.
DR HGNC; HGNC:4689; GUCY2D.
DR HPA; ENSG00000132518; Tissue enriched (retina).
DR MalaCards; GUCY2D; -.
DR MIM; 204000; phenotype.
DR MIM; 215500; phenotype.
DR MIM; 300071; phenotype.
DR MIM; 600179; gene.
DR MIM; 601777; phenotype.
DR MIM; 618555; phenotype.
DR neXtProt; NX_Q02846; -.
DR OpenTargets; ENSG00000132518; -.
DR Orphanet; 75377; Central areolar choroidal dystrophy.
DR Orphanet; 1872; Cone rod dystrophy.
DR Orphanet; 65; Leber congenital amaurosis.
DR PharmGKB; PA187; -.
DR VEuPathDB; HostDB:ENSG00000132518; -.
DR eggNOG; KOG1023; Eukaryota.
DR GeneTree; ENSGT00940000161326; -.
DR HOGENOM; CLU_001072_1_0_1; -.
DR InParanoid; Q02846; -.
DR OMA; YEGDRVW; -.
DR OrthoDB; 229634at2759; -.
DR PhylomeDB; Q02846; -.
DR TreeFam; TF106338; -.
DR BRENDA; 4.6.1.2; 2681.
DR PathwayCommons; Q02846; -.
DR Reactome; R-HSA-2514859; Inactivation, recovery and regulation of the phototransduction cascade.
DR SignaLink; Q02846; -.
DR BioGRID-ORCS; 3000; 10 hits in 1102 CRISPR screens.
DR GenomeRNAi; 3000; -.
DR Pharos; Q02846; Tbio.
DR PRO; PR:Q02846; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q02846; protein.
DR Bgee; ENSG00000132518; Expressed in esophagus mucosa and 91 other tissues.
DR Genevisible; Q02846; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0005640; C:nuclear outer membrane; TAS:ProtInc.
DR GO; GO:0097381; C:photoreceptor disc membrane; TAS:Reactome.
DR GO; GO:0001750; C:photoreceptor outer segment; IDA:UniProtKB.
DR GO; GO:0042622; C:photoreceptor outer segment membrane; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:InterPro.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0004383; F:guanylate cyclase activity; IDA:UniProtKB.
DR GO; GO:0001653; F:peptide receptor activity; IBA:GO_Central.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IEA:InterPro.
DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc.
DR GO; GO:0006182; P:cGMP biosynthetic process; IBA:GO_Central.
DR GO; GO:0019934; P:cGMP-mediated signaling; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0007168; P:receptor guanylyl cyclase signaling pathway; IBA:GO_Central.
DR GO; GO:0022400; P:regulation of rhodopsin mediated signaling pathway; TAS:Reactome.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0007601; P:visual perception; TAS:ProtInc.
DR CDD; cd07302; CHD; 1.
DR Gene3D; 3.30.70.1230; -; 1.
DR InterPro; IPR001054; A/G_cyclase.
DR InterPro; IPR018297; A/G_cyclase_CS.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR011645; HNOB_dom_associated.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR029787; Nucleotide_cyclase.
DR InterPro; IPR028082; Peripla_BP_I.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF00211; Guanylate_cyc; 1.
DR Pfam; PF07701; HNOBA; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR SMART; SM00044; CYCc; 1.
DR SUPFAM; SSF53822; SSF53822; 1.
DR SUPFAM; SSF55073; SSF55073; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 1.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW Cell projection; cGMP biosynthesis; Cone-rod dystrophy;
KW Congenital stationary night blindness; Disease variant; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; GTP-binding;
KW Leber congenital amaurosis; Lyase; Membrane; Nucleotide-binding;
KW Reference proteome; Sensory transduction; Signal; Transmembrane;
KW Transmembrane helix; Vision.
FT SIGNAL 1..51
FT /evidence="ECO:0000250|UniProtKB:P55203"
FT CHAIN 52..1103
FT /note="Retinal guanylyl cyclase 1"
FT /id="PRO_0000012381"
FT TOPO_DOM 52..462
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 463..487
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 488..1103
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 525..808
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 880..1010
FT /note="Guanylate cyclase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT REGION 1065..1103
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1085..1103
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 297
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 449
FT /note="Interchain"
FT /evidence="ECO:0000305"
FT DISULFID 457
FT /note="Interchain"
FT /evidence="ECO:0000305"
FT VARIANT 21
FT /note="W -> R (in dbSNP:rs9905402)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067168"
FT VARIANT 52
FT /note="A -> S (in LCA1; unknown pathological significance;
FT dbSNP:rs61749665)"
FT /evidence="ECO:0000269|PubMed:21602930,
FT ECO:0000269|PubMed:8944027"
FT /id="VAR_003435"
FT VARIANT 55
FT /note="T -> M (in LCA1; dbSNP:rs201414567)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067169"
FT VARIANT 103
FT /note="E -> V (in LCA1)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067170"
FT VARIANT 105
FT /note="C -> Y (in LCA1; does not affect basal guanylate
FT cyclase activity; reduces GUCA1A-induced guanylate cyclase
FT activity; dbSNP:rs61749669)"
FT /evidence="ECO:0000269|PubMed:11035546,
FT ECO:0000269|PubMed:15123990"
FT /id="VAR_023770"
FT VARIANT 312
FT /note="T -> M (in LCA1; dbSNP:rs61749673)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067171"
FT VARIANT 325
FT /note="L -> P (in LCA1; does not affect basal guanylate
FT cyclase activity; reduces GUCA1A-induced guanylate cyclase
FT activity; dbSNP:rs61749675)"
FT /evidence="ECO:0000269|PubMed:11035546,
FT ECO:0000269|PubMed:15123990"
FT /id="VAR_023771"
FT VARIANT 325
FT /note="L -> R (found in a patient with LCA1)"
FT /evidence="ECO:0000269|PubMed:17724218"
FT /id="VAR_067172"
FT VARIANT 328
FT /note="A -> V (in dbSNP:rs56280231)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042229"
FT VARIANT 331
FT /note="R -> S (in dbSNP:rs34596269)"
FT /id="VAR_049254"
FT VARIANT 362
FT /note="A -> S (in LCA1; dbSNP:rs61749677)"
FT /id="VAR_009129"
FT VARIANT 405..406
FT /note="LD -> PN (in LCA1)"
FT /id="VAR_067173"
FT VARIANT 431
FT /note="G -> D (in a metastatic melanoma sample; somatic
FT mutation; dbSNP:rs1451501407)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042230"
FT VARIANT 438
FT /note="R -> C (in LCA1; dbSNP:rs565948960)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067174"
FT VARIANT 507
FT /note="V -> M (in dbSNP:rs746002871)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042231"
FT VARIANT 565
FT /note="F -> S (in LCA1; loss of activity;
FT dbSNP:rs61749755)"
FT /evidence="ECO:0000269|PubMed:9888789"
FT /id="VAR_009131"
FT VARIANT 573
FT /note="I -> V (in LCA1; dbSNP:rs61749756)"
FT /id="VAR_009130"
FT VARIANT 602
FT /note="R -> W (in dbSNP:rs770740012)"
FT /id="VAR_049255"
FT VARIANT 640
FT /note="W -> L (in LCA1)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067175"
FT VARIANT 660
FT /note="R -> Q (in LCA1; dbSNP:rs61750162)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067176"
FT VARIANT 693
FT /note="A -> E (in dbSNP:rs35146471)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042232"
FT VARIANT 701
FT /note="P -> S (at homozygosity may be associated with Leber
FT congenital amaurosis in some populations;
FT dbSNP:rs34598902)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:17724218, ECO:0000269|PubMed:21602930"
FT /id="VAR_009132"
FT VARIANT 710
FT /note="A -> V (in LCA1; loss of basal and GUCA1A-induced
FT guanylate cyclase activity; does not affect endoplasmic
FT reticulum membrane localization; dbSNP:rs781725943)"
FT /evidence="ECO:0000269|PubMed:27475985,
FT ECO:0000269|PubMed:30319355"
FT /id="VAR_082624"
FT VARIANT 722
FT /note="R -> W (in dbSNP:rs34331388)"
FT /id="VAR_049256"
FT VARIANT 728
FT /note="D -> H (in LCA1)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067177"
FT VARIANT 734
FT /note="I -> A (in LCA1; requires 2 nucleotide
FT substitutions)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067178"
FT VARIANT 768
FT /note="R -> W (in LCA1 and CSNB1I; dbSNP:rs61750168)"
FT /evidence="ECO:0000269|PubMed:17724218,
FT ECO:0000269|PubMed:21602930, ECO:0000269|PubMed:29559409"
FT /id="VAR_067179"
FT VARIANT 782
FT /note="L -> H (in dbSNP:rs8069344)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_009133"
FT VARIANT 784
FT /note="M -> R (in LCA1; dbSNP:rs375010731)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067180"
FT VARIANT 795
FT /note="R -> Q (in LCA1; dbSNP:rs61750171)"
FT /evidence="ECO:0000269|PubMed:17724218"
FT /id="VAR_067181"
FT VARIANT 837..839
FT /note="ERT -> DCM (in CORD6)"
FT /evidence="ECO:0000269|PubMed:9683616"
FT /id="VAR_003438"
FT VARIANT 837
FT /note="E -> D (in CORD6; dbSNP:rs28933695)"
FT /evidence="ECO:0000269|PubMed:9618177"
FT /id="VAR_003436"
FT VARIANT 838
FT /note="R -> C (in CORD6; dbSNP:rs61750172)"
FT /evidence="ECO:0000269|PubMed:12552567,
FT ECO:0000269|PubMed:18487367, ECO:0000269|PubMed:25515582,
FT ECO:0000269|PubMed:9618177"
FT /id="VAR_003437"
FT VARIANT 838
FT /note="R -> G (in CORD6)"
FT /evidence="ECO:0000269|PubMed:18487367"
FT /id="VAR_071605"
FT VARIANT 838
FT /note="R -> H (in CORD6; dbSNP:rs61750173)"
FT /evidence="ECO:0000269|PubMed:12552567,
FT ECO:0000269|PubMed:18487367, ECO:0000269|PubMed:22194653,
FT ECO:0000269|PubMed:24480840"
FT /id="VAR_015373"
FT VARIANT 838
FT /note="R -> P (in CORD6; dbSNP:rs61750173)"
FT /evidence="ECO:0000269|PubMed:21552474"
FT /id="VAR_071606"
FT VARIANT 841
FT /note="E -> K (in CORD6; decreases basal and GUCA1A-induced
FT guanylate cyclase activity; inhibition by RD3 is less
FT effective; does not affect endoplasmic reticulum membrane
FT localization; dbSNP:rs1341592819)"
FT /evidence="ECO:0000269|PubMed:25515582,
FT ECO:0000269|PubMed:30319355"
FT /id="VAR_082625"
FT VARIANT 846
FT /note="K -> N (in CORD6; decreases basal and GUCA1A-induced
FT guanylate cyclase activity; inhibition by RD3 is less
FT effective; does not affect endoplasmic reticulum membrane
FT localization; dbSNP:rs1598150539)"
FT /evidence="ECO:0000269|PubMed:25515582,
FT ECO:0000269|PubMed:30319355"
FT /id="VAR_082626"
FT VARIANT 849
FT /note="T -> A (in CORD6)"
FT /evidence="ECO:0000269|PubMed:23734073"
FT /id="VAR_071607"
FT VARIANT 858
FT /note="P -> S (in LCA1; severely impairs basal and GUCA1A-
FT induced guanylate cyclase activity; dbSNP:rs61750176)"
FT /evidence="ECO:0000269|PubMed:11035546,
FT ECO:0000269|PubMed:15123990"
FT /id="VAR_009134"
FT VARIANT 873
FT /note="P -> R (in CORD6; loss basal and GUCA1A-induced
FT guanylate cyclase activity; does not affect endoplasmic
FT reticulum membrane localization; dbSNP:rs1567961680)"
FT /evidence="ECO:0000269|PubMed:30319355"
FT /id="VAR_082627"
FT VARIANT 902
FT /note="V -> L (in LCA1; increases basal and GUCA1A-induced
FT guanylate cyclase activity; inhibition by RD3 is less
FT effective; does not affect endoplasmic reticulum membrane
FT localization; dbSNP:rs1598150793)"
FT /evidence="ECO:0000269|PubMed:30319355"
FT /id="VAR_082628"
FT VARIANT 933
FT /note="V -> A (in CACD1; unknown pathological significance;
FT dbSNP:rs1567961904)"
FT /evidence="ECO:0000269|PubMed:22695961"
FT /id="VAR_080484"
FT VARIANT 949
FT /note="I -> T (in CORD6; dbSNP:rs267606857)"
FT /evidence="ECO:0000269|PubMed:20517349"
FT /id="VAR_071608"
FT VARIANT 954
FT /note="L -> P (in LCA1; severely impairs basal and GUCA1A
FT induced guanylate cyclase; dbSNP:rs61750182)"
FT /evidence="ECO:0000269|PubMed:12365911,
FT ECO:0000269|PubMed:15123990"
FT /id="VAR_009135"
FT VARIANT 1007
FT /note="S -> L (in LCA1)"
FT /evidence="ECO:0000269|PubMed:21602930"
FT /id="VAR_067182"
FT VARIANT 1027
FT /note="I -> IGI (in LCA1)"
FT /id="VAR_067183"
FT MUTAGEN 822
FT /note="R->P: Fails to become activated by GUCA1A and by
FT GUCA1B. Does not affect the binding to RP3."
FT /evidence="ECO:0000269|PubMed:26100624"
FT MUTAGEN 823
FT /note="M->R: Fails to become activated by GUCA1A and by
FT GUCA1B. Does not affect the binding to RP3."
FT /evidence="ECO:0000269|PubMed:26100624"
FT MUTAGEN 925
FT /note="E->K: Changes the substrate specificity from GTP to
FT ATP."
FT /evidence="ECO:0000269|PubMed:9600905"
FT MUTAGEN 997
FT /note="C->D: Changes the substrate specificity from GTP to
FT ATP."
FT /evidence="ECO:0000269|PubMed:9600905"
SQ SEQUENCE 1103 AA; 120059 MW; 28631557E7CBDFA4 CRC64;
MTACARRAGG LPDPGLCGPA WWAPSLPRLP RALPRLPLLL LLLLLQPPAL SAVFTVGVLG
PWACDPIFSR ARPDLAARLA AARLNRDPGL AGGPRFEVAL LPEPCRTPGS LGAVSSALAR
VSGLVGPVNP AACRPAELLA EEAGIALVPW GCPWTQAEGT TAPAVTPAAD ALYALLRAFG
WARVALVTAP QDLWVEAGRS LSTALRARGL PVASVTSMEP LDLSGAREAL RKVRDGPRVT
AVIMVMHSVL LGGEEQRYLL EAAEELGLTD GSLVFLPFDT IHYALSPGPE ALAALANSSQ
LRRAHDAVLT LTRHCPSEGS VLDSLRRAQE RRELPSDLNL QQVSPLFGTI YDAVFLLARG
VAEARAAAGG RWVSGAAVAR HIRDAQVPGF CGDLGGDEEP PFVLLDTDAA GDRLFATYML
DPARGSFLSA GTRMHFPRGG SAPGPDPSCW FDPNNICGGG LEPGLVFLGF LLVVGMGLAG
AFLAHYVRHR LLHMQMVSGP NKIILTVDDI TFLHPHGGTS RKVAQGSRSS LGARSMSDIR
SGPSQHLDSP NIGVYEGDRV WLKKFPGDQH IAIRPATKTA FSKLQELRHE NVALYLGLFL
ARGAEGPAAL WEGNLAVVSE HCTRGSLQDL LAQREIKLDW MFKSSLLLDL IKGIRYLHHR
GVAHGRLKSR NCIVDGRFVL KITDHGHGRL LEAQKVLPEP PRAEDQLWTA PELLRDPALE
RRGTLAGDVF SLAIIMQEVV CRSAPYAMLE LTPEEVVQRV RSPPPLCRPL VSMDQAPVEC
ILLMKQCWAE QPELRPSMDH TFDLFKNINK GRKTNIIDSM LRMLEQYSSN LEDLIRERTE
ELELEKQKTD RLLTQMLPPS VAEALKTGTP VEPEYFEQVT LYFSDIVGFT TISAMSEPIE
VVDLLNDLYT LFDAIIGSHD VYKVETIGDA YMVASGLPQR NGQRHAAEIA NMSLDILSAV
GTFRMRHMPE VPVRIRIGLH SGPCVAGVVG LTMPRYCLFG DTVNTASRME STGLPYRIHV
NLSTVGILRA LDSGYQVELR GRTELKGKGA EDTFWLVGRR GFNKPIPKPP DLQPGSSNHG
ISLQEIPPER RRKLEKARPG QFS
