ID TMPS6_HUMAN Reviewed; 811 AA. AC Q8IU80; B0QYB4; B0QYB7; B0QYB8; Q5TI06; Q6ICC2; Q6UXD8; Q8IUE2; Q8IXV8; DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot. DT 14-OCT-2008, sequence version 3. DT 27-MAR-2024, entry version 183. DE RecName: Full=Transmembrane protease serine 6; DE EC=3.4.21.-; DE AltName: Full=Matriptase-2; GN Name=TMPRSS6; ORFNames=UNQ354/PRO618; 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 [GENOMIC DNA / MRNA] (ISOFORM 1). RA Hooper J.D., Quigley J.P.; RT "TMPRSS6, a new type II transmembrane serine protease."; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ALA-736. 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84; RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., RA Beare D.M., Dunham I.; RT "A genome annotation-driven approach to cloning the human ORFeome."; RL Genome Biol. 5:R84.1-R84.11(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10591208; DOI=10.1038/990031; RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M., RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C., RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E., RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C., RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G., RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V., RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E., RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F., RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M., RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A., RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D., RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S., RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E., RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A., RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L., RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P., RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P., RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q., RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J., RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J., RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D., RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T., RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L., RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J., RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E., RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P., RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y., RA Wright H.; RT "The DNA sequence of human chromosome 22."; RL Nature 402:489-495(1999). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Brain; 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 [6] RP RETRACTED PAPER. RC TISSUE=Fetal liver; RX PubMed=12149247; DOI=10.1074/jbc.m203007200; RA Velasco G., Cal S., Quesada V., Sanchez L.M., Lopez-Otin C.; RT "Matriptase-2, a membrane-bound mosaic serine proteinase predominantly RT expressed in human liver and showing degrading activity against RT extracellular matrix proteins."; RL J. Biol. Chem. 277:37637-37646(2002). RN [7] RP RETRACTION NOTICE OF PUBMED:12149247. RX PubMed=30808001; DOI=10.1074/jbc.w118.007324; RA Velasco G., Cal S., Quesada V., Sanchez L.M., Lopez-Otin C.; RL J. Biol. Chem. 294:1430-1430(2019). RN [8] RP REVIEW. RX PubMed=12784999; DOI=10.1023/a:1023003616848; RA Netzel-Arnett S., Hooper J.D., Szabo R., Madison E.L., Quigley J.P., RA Bugge T.H., Antalis T.M.; RT "Membrane anchored serine proteases: a rapidly expanding group of cell RT surface proteolytic enzymes with potential roles in cancer."; RL Cancer Metastasis Rev. 22:237-258(2003). RN [9] RP FUNCTION, INTERACTION WITH HJV, SUBCELLULAR LOCATION, PROTEOLYTIC RP PROCESSING, AND CHARACTERIZATION OF VARIANT IRIDA CYS-774. RX PubMed=18976966; DOI=10.1016/j.cmet.2008.09.012; RA Silvestri L., Pagani A., Nai A., De Domenico I., Kaplan J., Camaschella C.; RT "The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by RT cleaving membrane hemojuvelin."; RL Cell Metab. 8:502-511(2008). RN [10] RP REVIEW. RX PubMed=17981570; DOI=10.2741/2702; RA Ramsay A.J., Reid J.C., Velasco G., Quigley J.P., Hooper J.D.; RT "The type II transmembrane serine protease matriptase-2 -- identification, RT structural features, enzymology, expression pattern and potential roles."; RL Front. Biosci. 13:569-579(2008). RN [11] RP INVOLVEMENT IN IRIDA. RX PubMed=18603562; DOI=10.3324/haematol.13342; RA Melis M.A., Cau M., Congiu R., Sole G., Barella S., Cao A., Westerman M., RA Cazzola M., Galanello R.; RT "A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease RT that suppresses hepcidin production, in familial iron deficiency anemia RT refractory to oral iron."; RL Haematologica 93:1473-1479(2008). RN [12] RP INTERACTION WITH HJV, VARIANTS IRIDA ASN-521 AND LYS-522, AND RP CHARACTERIZATION OF VARIANTS IRIDA ARG-442; ASN-521 AND LYS-522. RX PubMed=19357398; DOI=10.1182/blood-2008-12-195594; RA Silvestri L., Guillem F., Pagani A., Nai A., Oudin C., Silva M., RA Toutain F., Kannengiesser C., Beaumont C., Camaschella C., Grandchamp B.; RT "Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 RT mutations associated with iron-refractory iron deficiency anemia."; RL Blood 113:5605-5608(2009). RN [13] RP INVOLVEMENT IN IRIDA. RX PubMed=19747362; DOI=10.1111/j.1365-2141.2009.07879.x; RA Edison E.S., Athiyarath R., Rajasekar T., Westerman M., Srivastava A., RA Chandy M.; RT "A novel splice site mutation c.2278 (-1) G>C in the TMPRSS6 gene causes RT deletion of the substrate binding site of the serine protease resulting in RT refractory iron deficiency anaemia."; RL Br. J. Haematol. 147:766-769(2009). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, IDENTIFICATION BY RP MASS SPECTROMETRY, AND MUTAGENESIS OF SER-762. RX PubMed=20518742; DOI=10.1042/bj20091565; RA Stirnberg M., Maurer E., Horstmeyer A., Kolp S., Frank S., Bald T., RA Arenz K., Janzer A., Prager K., Wunderlich P., Walter J., Gutschow M.; RT "Proteolytic processing of the serine protease matriptase-2: identification RT of the cleavage sites required for its autocatalytic release from the cell RT surface."; RL Biochem. J. 430:87-95(2010). RN [15] RP INTERACTION WITH HJV, VARIANT IRIDA CYS-141, AND CHARACTERIZATION OF RP VARIANT IRIDA CYS-141. RX PubMed=20704562; DOI=10.1042/bj20100668; RA Altamura S., D'Alessio F., Selle B., Muckenthaler M.U.; RT "A novel TMPRSS6 mutation that prevents protease auto-activation causes RT IRIDA."; RL Biochem. J. 431:363-371(2010). RN [16] RP VARIANTS [LARGE SCALE ANALYSIS] HIS-223 AND SER-234. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [17] RP VARIANTS IRIDA ARG-442; ASN-521 AND CYS-774, AND FUNCTION IN IRON RP HOMEOSTASIS. RX PubMed=18408718; DOI=10.1038/ng.130; RA Finberg K.E., Heeney M.M., Campagna D.R., Aydinok Y., Pearson H.A., RA Hartman K.R., Mayo M.M., Samuel S.M., Strouse J.J., Markianos K., RA Andrews N.C., Fleming M.D.; RT "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia RT (IRIDA)."; RL Nat. Genet. 40:569-571(2008). RN [18] RP VARIANT IRIDA LEU-304. RX PubMed=19708871; DOI=10.1111/j.1600-0609.2009.01340.x; RA Tchou I., Diepold M., Pilotto P.A., Swinkels D., Neerman-Arbez M., RA Beris P.; RT "Haematologic data, iron parameters and molecular findings in two new cases RT of iron-refractory iron deficiency anaemia."; RL Eur. J. Haematol. 83:595-602(2009). RN [19] RP VARIANT IRIDA ASP-118, AND CHARACTERIZATION OF VARIANT IRIDA ASP-118. RX PubMed=19592582; DOI=10.1093/hmg/ddp315; RA Ramsay A.J., Quesada V., Sanchez M., Garabaya C., Sarda M.P., Baiget M., RA Remacha A., Velasco G., Lopez-Otin C.; RT "Matriptase-2 mutations in iron-refractory iron deficiency anemia patients RT provide new insights into protease activation mechanisms."; RL Hum. Mol. Genet. 18:3673-3683(2009). RN [20] RP VARIANTS ASP-228; GLU-253; TRP-446; PHE-674; ALA-736 AND ILE-795. RX PubMed=19818657; DOI=10.1016/j.bcmd.2009.09.001; RA Beutler E., Van Geet C., te Loo D.M., Gelbart T., Crain K., Truksa J., RA Lee P.L.; RT "Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia."; RL Blood Cells Mol. Dis. 44:16-21(2010). RN [21] RP VARIANTS IRIDA CYS-141; THR-212; GLN-271; LEU-304 AND SER-510, AND RP CHARACTERIZATION OF VARIANTS IRIDA THR-212 AND GLN-271. RX PubMed=20232450; DOI=10.1002/humu.21243; RA De Falco L., Totaro F., Nai A., Pagani A., Girelli D., Silvestri L., RA Piscopo C., Campostrini N., Dufour C., Al Manjomi F., Minkov M., RA Van Vuurden D.G., Feliu A., Kattamis A., Camaschella C., Iolascon A.; RT "Novel TMPRSS6 mutations associated with iron-refractory iron deficiency RT anemia (IRIDA)."; RL Hum. Mutat. 31:E1390-E1405(2010). RN [22] RP VARIANT GLU-253. RX PubMed=21643693; DOI=10.1007/s12185-011-0881-0; RA Sato T., Iyama S., Murase K., Kamihara Y., Ono K., Kikuchi S., Takada K., RA Miyanishi K., Sato Y., Takimoto R., Kobune M., Kato J.; RT "Novel missense mutation in the TMPRSS6 gene in a Japanese female with RT iron-refractory iron deficiency anemia."; RL Int. J. Hematol. 94:101-103(2011). RN [23] RP VARIANTS IRIDA LYS-114; PRO-235; CYS-418 AND ALA-765, MUTAGENESIS OF RP ARG-576 AND SER-762, AND CHARACTERIZATION OF VARIANTS IRIDA LYS-114; RP PRO-235; CYS-418 AND ALA-765. RX PubMed=22581667; DOI=10.1002/humu.22116; RA Guillem F., Kannengiesser C., Oudin C., Lenoir A., Matak P., Donadieu J., RA Isidor B., Mechinaud F., Aguilar-Martinez P., Beaumont C., Vaulont S., RA Grandchamp B., Nicolas G.; RT "Inactive matriptase-2 mutants found in IRIDA patients still repress RT hepcidin in a transfection assay despite having lost their serine protease RT activity."; RL Hum. Mutat. 33:1388-1396(2012). RN [24] RP VARIANT IRIDA ARG-603. RX PubMed=21618415; DOI=10.1002/pbc.23190; RA Choi H.S., Yang H.R., Song S.H., Seo J.Y., Lee K.O., Kim H.J.; RT "A novel mutation Gly603Arg of TMPRSS6 in a Korean female with iron- RT refractory iron deficiency anemia."; RL Pediatr. Blood Cancer 58:640-642(2012). RN [25] RP VARIANTS IRIDA CYS-247; ASN-287; LEU-304; PHE-335; ARG-510; GLY-521; RP ARG-590; TRP-597; GLY-605; ARG-606 AND THR-623, CHARACTERIZATION OF RP VARIANTS IRIDA CYS-247; ASN-287; PHE-335; ARG-510; ARG-590; TRP-597; RP GLY-605 AND ARG-606, FUNCTION, SUBCELLULAR LOCATION, AND PROTEOLYTIC RP PROCESSING. RX PubMed=25156943; DOI=10.1002/humu.22632; RA De Falco L., Silvestri L., Kannengiesser C., Moran E., Oudin C., Rausa M., RA Bruno M., Aranda J., Argiles B., Yenicesu I., Falcon-Rodriguez M., RA Yilmaz-Keskin E., Kocak U., Beaumont C., Camaschella C., Iolascon A., RA Grandchamp B., Sanchez M.; RT "Functional and clinical impact of novel TMPRSS6 variants in iron- RT refractory iron-deficiency anemia patients and genotype-phenotype RT studies."; RL Hum. Mutat. 35:1321-1329(2014). RN [26] RP CHARACTERIZATION OF VARIANTS IRIDA CYS-141; THR-212; GLN-271; ARG-442 AND RP SER-510, AND SUBCELLULAR LOCATION. RX PubMed=25588876; DOI=10.1152/ajpcell.00264.2014; RA McDonald C.J., Ostini L., Bennett N.C., Subramaniam N., Hooper J., RA Velasco G., Wallace D.F., Subramaniam V.N.; RT "Functional analysis of Matriptase-2 mutations and domains: Insights into RT the molecular basis of iron refractory iron deficiency anemia."; RL Am. J. Physiol. 308:C539-C547(2015). CC -!- FUNCTION: Membrane-bound serine protease (PubMed:18976966, CC PubMed:20518742, PubMed:25156943, PubMed:25588876). Through the CC cleavage of cell surface HJV, a regulator of the expression of the iron CC absorption-regulating hormone hepicidin/HAMP, plays a role in iron CC homeostasis (PubMed:25156943, PubMed:18408718, PubMed:18976966). CC {ECO:0000269|PubMed:18408718, ECO:0000269|PubMed:18976966, CC ECO:0000269|PubMed:20518742, ECO:0000269|PubMed:25156943, CC ECO:0000269|PubMed:25588876, ECO:0000303|PubMed:25156943}. CC -!- SUBUNIT: Interacts with HJV. {ECO:0000269|PubMed:18976966, CC ECO:0000269|PubMed:19357398, ECO:0000269|PubMed:20704562}. CC -!- INTERACTION: CC Q8IU80-2; Q86V38: ATN1; NbExp=3; IntAct=EBI-25839648, EBI-11954292; CC Q8IU80-2; P02489: CRYAA; NbExp=3; IntAct=EBI-25839648, EBI-6875961; CC Q8IU80-2; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-25839648, EBI-356015; CC Q8IU80-2; Q92876: KLK6; NbExp=3; IntAct=EBI-25839648, EBI-2432309; CC Q8IU80-4; Q6ZVN8: HJV; NbExp=3; IntAct=EBI-11686560, EBI-10900704; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18976966, CC ECO:0000269|PubMed:20518742, ECO:0000269|PubMed:25588876}; Single-pass CC type II membrane protein {ECO:0000269|PubMed:20518742}. Note=The CC processed, activated two-chains form is released in the extracellular CC space. {ECO:0000269|PubMed:25156943}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q8IU80-4; Sequence=Displayed; CC Name=2; CC IsoId=Q8IU80-1; Sequence=VSP_035562; CC Name=3; CC IsoId=Q8IU80-2; Sequence=VSP_008379, VSP_008380; CC Name=4; CC IsoId=Q8IU80-5; Sequence=VSP_035562, VSP_035563; CC -!- DOMAIN: Cytoplasmic domain mediates HAMP suppression via proximal CC promoter element(s). {ECO:0000250}. CC -!- PTM: The single-chain zymogen undergoes autoproteolytic processing CC (PubMed:20518742, PubMed:25156943, PubMed:18976966). This results in CC TMPRSS6 shedding from the cell surface and conversion into an activated CC two-chains form which is released extracellularly (PubMed:20518742, CC PubMed:25156943, PubMed:18976966). The process involves a trans- CC activation mechanism that requires TMPRSS6 oligomerization CC (PubMed:20518742, PubMed:25156943). {ECO:0000269|PubMed:18976966, CC ECO:0000269|PubMed:20518742, ECO:0000269|PubMed:25156943}. CC -!- DISEASE: Iron-refractory iron deficiency anemia (IRIDA) [MIM:206200]: CC Key features include congenital hypochromic microcytic anemia, very low CC mean corpuscular erythrocyte volume, low transferrin saturation, CC abnormal iron absorption characterized by no hematologic improvement CC following treatment with oral iron, and abnormal iron utilization CC characterized by a sluggish, incomplete response to parenteral iron. CC {ECO:0000269|PubMed:18408718, ECO:0000269|PubMed:18603562, CC ECO:0000269|PubMed:18976966, ECO:0000269|PubMed:19357398, CC ECO:0000269|PubMed:19592582, ECO:0000269|PubMed:19708871, CC ECO:0000269|PubMed:19747362, ECO:0000269|PubMed:20232450, CC ECO:0000269|PubMed:20704562, ECO:0000269|PubMed:21618415, CC ECO:0000269|PubMed:22581667, ECO:0000269|PubMed:25156943, CC ECO:0000269|PubMed:25588876}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Mutations leading to CC abrogation of TMPRSS6 activity are associated with IRIDA due to CC elevated levels of hepcidin, a negative regulator of plasma iron pool CC (PubMed:20232450). {ECO:0000269|PubMed:20232450}. CC -!- SIMILARITY: Belongs to the peptidase S1 family. {ECO:0000255|PROSITE- CC ProRule:PRU00274}. CC -!- CAUTION: A study described a function as serine protease towards CC extracellular matrix proteins in the liver; however, this article was CC later retracted. {ECO:0000269|PubMed:12149247, CC ECO:0000305|PubMed:30808001}. 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; AY055383; AAL16413.1; -; Genomic_DNA. DR EMBL; AY055384; AAL16414.1; -; mRNA. DR EMBL; AY358398; AAQ88764.1; -; mRNA. DR EMBL; CR456446; CAG30332.1; -; mRNA. DR EMBL; AL022314; CAQ07360.1; -; Genomic_DNA. DR EMBL; AL022314; CAQ07361.1; -; Genomic_DNA. DR EMBL; AL022314; CAQ07363.1; -; Genomic_DNA. DR EMBL; AL022314; CAQ07364.1; -; Genomic_DNA. DR EMBL; AJ319876; CAC85953.1; -; mRNA. DR EMBL; BC039082; AAH39082.1; -; mRNA. DR CCDS; CCDS74856.1; -. [Q8IU80-1] DR CCDS; CCDS74857.1; -. [Q8IU80-5] DR RefSeq; NP_001275929.1; NM_001289000.1. [Q8IU80-5] DR RefSeq; NP_001275930.1; NM_001289001.1. [Q8IU80-1] DR RefSeq; NP_705837.1; NM_153609.3. [Q8IU80-1] DR AlphaFoldDB; Q8IU80; -. DR SMR; Q8IU80; -. DR BioGRID; 127898; 2. DR IntAct; Q8IU80; 7. DR MINT; Q8IU80; -. DR STRING; 9606.ENSP00000384964; -. DR BindingDB; Q8IU80; -. DR ChEMBL; CHEMBL1795139; -. DR GuidetoPHARMACOLOGY; 2422; -. DR MEROPS; S01.308; -. DR GlyCosmos; Q8IU80; 7 sites, No reported glycans. DR GlyGen; Q8IU80; 7 sites. DR iPTMnet; Q8IU80; -. DR PhosphoSitePlus; Q8IU80; -. DR BioMuta; TMPRSS6; -. DR DMDM; 209572718; -. DR jPOST; Q8IU80; -. DR MassIVE; Q8IU80; -. DR PaxDb; 9606-ENSP00000371211; -. DR PeptideAtlas; Q8IU80; -. DR ProteomicsDB; 70516; -. [Q8IU80-4] DR ProteomicsDB; 70517; -. [Q8IU80-1] DR ProteomicsDB; 70518; -. [Q8IU80-2] DR ProteomicsDB; 70519; -. [Q8IU80-5] DR Antibodypedia; 25860; 184 antibodies from 21 providers. DR DNASU; 164656; -. DR Ensembl; ENST00000346753.9; ENSP00000334962.6; ENSG00000187045.19. [Q8IU80-1] DR Ensembl; ENST00000381792.6; ENSP00000371211.2; ENSG00000187045.19. [Q8IU80-5] DR Ensembl; ENST00000406725.6; ENSP00000385453.1; ENSG00000187045.19. [Q8IU80-1] DR Ensembl; ENST00000406856.7; ENSP00000384964.1; ENSG00000187045.19. [Q8IU80-5] DR Ensembl; ENST00000676104.1; ENSP00000501573.1; ENSG00000187045.19. [Q8IU80-1] DR GeneID; 164656; -. DR KEGG; hsa:164656; -. DR MANE-Select; ENST00000676104.1; ENSP00000501573.1; NM_001374504.1; NP_001361433.1. [Q8IU80-1] DR UCSC; uc003aqs.3; human. [Q8IU80-4] DR AGR; HGNC:16517; -. DR CTD; 164656; -. DR DisGeNET; 164656; -. DR GeneCards; TMPRSS6; -. DR HGNC; HGNC:16517; TMPRSS6. DR HPA; ENSG00000187045; Tissue enriched (liver). DR MalaCards; TMPRSS6; -. DR MIM; 206200; phenotype. DR MIM; 609862; gene. DR neXtProt; NX_Q8IU80; -. DR OpenTargets; ENSG00000187045; -. DR Orphanet; 209981; IRIDA syndrome. DR PharmGKB; PA134880399; -. DR VEuPathDB; HostDB:ENSG00000187045; -. DR eggNOG; KOG3627; Eukaryota. DR GeneTree; ENSGT00940000160104; -. DR HOGENOM; CLU_006842_19_3_1; -. DR InParanoid; Q8IU80; -. DR OMA; WFALQIP; -. DR OrthoDB; 4629979at2759; -. DR PhylomeDB; Q8IU80; -. DR TreeFam; TF330647; -. DR BRENDA; 3.4.21.109; 2681. DR PathwayCommons; Q8IU80; -. DR Reactome; R-HSA-1442490; Collagen degradation. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR SignaLink; Q8IU80; -. DR BioGRID-ORCS; 164656; 13 hits in 1145 CRISPR screens. DR ChiTaRS; TMPRSS6; human. DR GeneWiki; TMPRSS6; -. DR GenomeRNAi; 164656; -. DR Pharos; Q8IU80; Tchem. DR PRO; PR:Q8IU80; -. DR Proteomes; UP000005640; Chromosome 22. DR RNAct; Q8IU80; Protein. DR Bgee; ENSG00000187045; Expressed in right lobe of liver and 118 other cell types or tissues. DR ExpressionAtlas; Q8IU80; baseline and differential. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0004222; F:metalloendopeptidase activity; TAS:Reactome. DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro. DR GO; GO:0030509; P:BMP signaling pathway; IEA:Ensembl. DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome. DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome. DR GO; GO:0006879; P:intracellular iron ion homeostasis; ISS:BHF-UCL. DR GO; GO:0033619; P:membrane protein proteolysis; IMP:UniProtKB. DR GO; GO:0060586; P:multicellular organismal-level iron ion homeostasis; IMP:UniProtKB. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IEA:Ensembl. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0097264; P:self proteolysis; IMP:UniProtKB. DR CDD; cd00041; CUB; 1. DR CDD; cd00112; LDLa; 3. DR CDD; cd00190; Tryp_SPc; 1. DR Gene3D; 4.10.400.10; Low-density Lipoprotein Receptor; 3. DR Gene3D; 3.30.70.960; SEA domain; 1. DR Gene3D; 2.60.120.290; Spermadhesin, CUB domain; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 1. DR InterPro; IPR000859; CUB_dom. DR InterPro; IPR036055; LDL_receptor-like_sf. DR InterPro; IPR002172; LDrepeatLR_classA_rpt. DR InterPro; IPR017118; Pept_S1A_matriptase-2. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin. DR InterPro; IPR001314; Peptidase_S1A. DR InterPro; IPR000082; SEA_dom. DR InterPro; IPR036364; SEA_dom_sf. DR InterPro; IPR035914; Sperma_CUB_dom_sf. DR InterPro; IPR001254; Trypsin_dom. DR InterPro; IPR018114; TRYPSIN_HIS. DR InterPro; IPR033116; TRYPSIN_SER. DR PANTHER; PTHR24252; ACROSIN-RELATED; 1. DR PANTHER; PTHR24252:SF12; LOW QUALITY PROTEIN: TRANSMEMBRANE PROTEASE SERINE 6; 1. DR Pfam; PF00057; Ldl_recept_a; 2. DR Pfam; PF01390; SEA; 1. DR Pfam; PF00089; Trypsin; 1. DR PIRSF; PIRSF037135; Matriptase-2; 1. DR PRINTS; PR00722; CHYMOTRYPSIN. DR SMART; SM00192; LDLa; 3. DR SMART; SM00020; Tryp_SPc; 1. DR SUPFAM; SSF57424; LDL receptor-like module; 3. DR SUPFAM; SSF82671; SEA domain; 1. DR SUPFAM; SSF49854; Spermadhesin, CUB domain; 2. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS01180; CUB; 1. DR PROSITE; PS01209; LDLRA_1; 2. DR PROSITE; PS50068; LDLRA_2; 3. DR PROSITE; PS50024; SEA; 1. DR PROSITE; PS50240; TRYPSIN_DOM; 1. DR PROSITE; PS00134; TRYPSIN_HIS; 1. DR PROSITE; PS00135; TRYPSIN_SER; 1. DR Genevisible; Q8IU80; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Disease variant; Disulfide bond; KW Glycoprotein; Hydrolase; Membrane; Protease; Reference proteome; Repeat; KW Serine protease; Signal-anchor; Transmembrane; Transmembrane helix; KW Zymogen. FT CHAIN 1..811 FT /note="Transmembrane protease serine 6" FT /id="PRO_0000088696" FT TOPO_DOM 1..55 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 56..76 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 77..811 FT /note="Extracellular" FT /evidence="ECO:0000255" FT DOMAIN 84..209 FT /note="SEA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00188" FT DOMAIN 213..336 FT /note="CUB 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059" FT DOMAIN 335..452 FT /note="CUB 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059" FT DOMAIN 457..489 FT /note="LDL-receptor class A 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 490..526 FT /note="LDL-receptor class A 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 530..567 FT /note="LDL-receptor class A 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 577..811 FT /note="Peptidase S1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT ACT_SITE 617 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT ACT_SITE 668 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT ACT_SITE 762 FT /note="Charge relay system" FT /evidence="ECO:0000250" FT CARBOHYD 136 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 184 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 216 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 338 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 433 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 453 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 518 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 335..366 FT /evidence="ECO:0000250" FT DISULFID 458..470 FT /evidence="ECO:0000250" FT DISULFID 464..480 FT /evidence="ECO:0000250" FT DISULFID 474..489 FT /evidence="ECO:0000250" FT DISULFID 491..503 FT /evidence="ECO:0000250" FT DISULFID 497..516 FT /evidence="ECO:0000250" FT DISULFID 510..525 FT /evidence="ECO:0000250" FT DISULFID 531..543 FT /evidence="ECO:0000250" FT DISULFID 538..557 FT /evidence="ECO:0000250" FT DISULFID 551..566 FT /evidence="ECO:0000250" FT DISULFID 602..618 FT /evidence="ECO:0000250" FT DISULFID 702..768 FT /evidence="ECO:0000250" FT DISULFID 733..747 FT /evidence="ECO:0000250" FT DISULFID 758..787 FT /evidence="ECO:0000250" FT VAR_SEQ 1..9 FT /note="Missing (in isoform 2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:12975309, FT ECO:0000303|PubMed:15461802" FT /id="VSP_035562" FT VAR_SEQ 409..461 FT /note="LCGLRILQPYAERIPVVATAGITINFTSQISLTGPGVRVHYGLYNQSDPCPG FT E -> YHFLSSLWLPFLPPPPSLPSSTVTPSLEAQVPNLRGAARGASRGWGWCQACCP FT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_008379" FT VAR_SEQ 462..811 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_008380" FT VAR_SEQ 714 FT /note="G -> ALRADAVALFYGWRNQGSETCCC (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15461802" FT /id="VSP_035563" FT VARIANT 114 FT /note="E -> K (in IRIDA; does not undergo proteolytic FT processing; loss of activity; dbSNP:rs199474803)" FT /evidence="ECO:0000269|PubMed:22581667" FT /id="VAR_068665" FT VARIANT 118 FT /note="A -> D (in IRIDA; results in reduced inhibition of FT HAMP promoter; dbSNP:rs267607121)" FT /evidence="ECO:0000269|PubMed:19592582" FT /id="VAR_068666" FT VARIANT 141 FT /note="Y -> C (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; does not undergo proteolytic FT processing; impaired localization to the cell membrane; FT able to interact with HJV; dbSNP:rs1430692214)" FT /evidence="ECO:0000269|PubMed:20232450, FT ECO:0000269|PubMed:20704562, ECO:0000269|PubMed:25588876" FT /id="VAR_064075" FT VARIANT 212 FT /note="I -> T (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; reduced localization to the cell FT membrane; no effect on catalytic activity; FT dbSNP:rs776877803)" FT /evidence="ECO:0000269|PubMed:20232450, FT ECO:0000269|PubMed:25588876" FT /id="VAR_064076" FT VARIANT 223 FT /note="R -> H (in a breast cancer sample; somatic mutation; FT dbSNP:rs749106338)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036296" FT VARIANT 228 FT /note="G -> D (in dbSNP:rs754848810)" FT /evidence="ECO:0000269|PubMed:19818657" FT /id="VAR_068667" FT VARIANT 234 FT /note="R -> S (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036297" FT VARIANT 235 FT /note="L -> P (in IRIDA; does not undergo proteolytic FT processing; loss of activity; dbSNP:rs199474802)" FT /evidence="ECO:0000269|PubMed:22581667" FT /id="VAR_068668" FT VARIANT 247 FT /note="W -> C (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072901" FT VARIANT 253 FT /note="K -> E (in dbSNP:rs2235324)" FT /evidence="ECO:0000269|PubMed:19818657, FT ECO:0000269|PubMed:21643693" FT /id="VAR_051841" FT VARIANT 262 FT /note="E -> K (in dbSNP:rs2235324)" FT /id="VAR_044434" FT VARIANT 271 FT /note="R -> Q (in IRIDA; no effect on HJV-mediated FT inhibition of HAMP transcription; no effect on localization FT to the cell membrane; no effect on catalytic activity; HJV FT processing is not affected; dbSNP:rs776180387)" FT /evidence="ECO:0000269|PubMed:20232450, FT ECO:0000269|PubMed:25588876" FT /id="VAR_064077" FT VARIANT 287 FT /note="T -> N (in IRIDA; no effect on HJV-mediated FT inhibition of HAMP transcription; no effect on catalytic FT activity; autoproteolytic and HJV processing are not FT affected; dbSNP:rs1449962575)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072902" FT VARIANT 288 FT /note="S -> L (in dbSNP:rs5995378)" FT /id="VAR_051842" FT VARIANT 304 FT /note="S -> L (in IRIDA; dbSNP:rs1373272804)" FT /evidence="ECO:0000269|PubMed:19708871, FT ECO:0000269|PubMed:20232450, ECO:0000269|PubMed:25156943" FT /id="VAR_064078" FT VARIANT 335 FT /note="C -> F (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072903" FT VARIANT 418 FT /note="Y -> C (in IRIDA; does not undergo proteolytic FT processing; loss of activity; dbSNP:rs199474804)" FT /evidence="ECO:0000269|PubMed:22581667" FT /id="VAR_068669" FT VARIANT 442 FT /note="G -> R (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; reduced localization to the cell FT membrane; altered catalytic activity; autoproteolytic FT processing is reduced but it retains the ability to process FT HJV; able to interact with HJV; dbSNP:rs137853119)" FT /evidence="ECO:0000269|PubMed:18408718, FT ECO:0000269|PubMed:19357398, ECO:0000269|PubMed:25588876" FT /id="VAR_044435" FT VARIANT 446 FT /note="R -> W (in dbSNP:rs117576908)" FT /evidence="ECO:0000269|PubMed:19818657" FT /id="VAR_068670" FT VARIANT 510 FT /note="C -> R (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072904" FT VARIANT 510 FT /note="C -> S (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; reduced localization to the cell FT membrane; loss of catalytic activity; no ability to process FT HJV)" FT /evidence="ECO:0000269|PubMed:20232450, FT ECO:0000269|PubMed:25588876" FT /id="VAR_064079" FT VARIANT 521 FT /note="D -> G (in IRIDA)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072905" FT VARIANT 521 FT /note="D -> N (in IRIDA; reduced expression at the cell FT surface; partially retained in the Golgi apparatus; does FT not undergo proteolytic processing; able to interact with FT HJV; results in reduced inhibition of HAMP promoter; FT dbSNP:rs137853120)" FT /evidence="ECO:0000269|PubMed:18408718, FT ECO:0000269|PubMed:19357398" FT /id="VAR_044436" FT VARIANT 522 FT /note="E -> K (in IRIDA; reduced expression at the cell FT surface; partially retained in the Golgi apparatus; does FT not undergo proteolytic processing; able to interact with FT HJV; results in reduced inhibition of HAMP promoter; FT dbSNP:rs387907018)" FT /evidence="ECO:0000269|PubMed:19357398" FT /id="VAR_068671" FT VARIANT 590 FT /note="W -> R (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired; FT dbSNP:rs770897887)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072906" FT VARIANT 597 FT /note="R -> W (in IRIDA; slightly reduced HJV-mediated FT inhibition of HAMP transcription; loss of catalytic FT activity; autoproteolytic and HJV processing are FT significantly reduced; dbSNP:rs773272073)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072907" FT VARIANT 603 FT /note="G -> R (in IRIDA; dbSNP:rs769083817)" FT /evidence="ECO:0000269|PubMed:21618415" FT /id="VAR_068672" FT VARIANT 605 FT /note="A -> G (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072908" FT VARIANT 606 FT /note="L -> R (in IRIDA; reduced HJV-mediated inhibition of FT HAMP transcription; loss of catalytic activity; FT autoproteolytic and HJV processing are impaired)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072909" FT VARIANT 623 FT /note="S -> T (in IRIDA)" FT /evidence="ECO:0000269|PubMed:25156943" FT /id="VAR_072910" FT VARIANT 674 FT /note="L -> F" FT /evidence="ECO:0000269|PubMed:19818657" FT /id="VAR_068673" FT VARIANT 736 FT /note="V -> A (in dbSNP:rs855791)" FT /evidence="ECO:0000269|PubMed:12975309, FT ECO:0000269|PubMed:19818657" FT /id="VAR_051843" FT VARIANT 763 FT /note="G -> D (in dbSNP:rs11703011)" FT /id="VAR_051844" FT VARIANT 765 FT /note="P -> A (in IRIDA; severely reduced proteolytic FT processing; loss of activity; dbSNP:rs199474805)" FT /evidence="ECO:0000269|PubMed:22581667" FT /id="VAR_068674" FT VARIANT 774 FT /note="R -> C (in IRIDA; reduced proteolytic processing; FT reduced expression to plasma membrane; does not affect FT binding to HJV; dbSNP:rs776069764)" FT /evidence="ECO:0000269|PubMed:18408718, FT ECO:0000269|PubMed:18976966" FT /id="VAR_044437" FT VARIANT 795 FT /note="V -> I (in dbSNP:rs139105452)" FT /evidence="ECO:0000269|PubMed:19818657" FT /id="VAR_068675" FT MUTAGEN 576 FT /note="R->A: Does not undergo proteolytic processing." FT /evidence="ECO:0000269|PubMed:22581667" FT MUTAGEN 762 FT /note="S->A: Does not undergo proteolytic processing." FT /evidence="ECO:0000269|PubMed:20518742, FT ECO:0000269|PubMed:22581667" FT CONFLICT Q8IU80-2:430 FT /note="T -> I (in Ref. 4; CAQ07364)" FT /evidence="ECO:0000305" SQ SEQUENCE 811 AA; 90000 MW; 7EEF193F655DDE9D CRC64; MLLLFHSKRM PVAEAPQVAG GQGDGGDGEE AEPEGMFKAC EDSKRKARGY LRLVPLFVLL ALLVLASAGV LLWYFLGYKA EVMVSQVYSG SLRVLNRHFS QDLTRRESSA FRSETAKAQK MLKELITSTR LGTYYNSSSV YSFGEGPLTC FFWFILQIPE HRRLMLSPEV VQALLVEELL STVNSSAAVP YRAEYEVDPE GLVILEASVK DIAALNSTLG CYRYSYVGQG QVLRLKGPDH LASSCLWHLQ GPKDLMLKLR LEWTLAECRD RLAMYDVAGP LEKRLITSVY GCSRQEPVVE VLASGAIMAV VWKKGLHSYY DPFVLSVQPV VFQACEVNLT LDNRLDSQGV LSTPYFPSYY SPQTHCSWHL TVPSLDYGLA LWFDAYALRR QKYDLPCTQG QWTIQNRRLC GLRILQPYAE RIPVVATAGI TINFTSQISL TGPGVRVHYG LYNQSDPCPG EFLCSVNGLC VPACDGVKDC PNGLDERNCV CRATFQCKED STCISLPKVC DGQPDCLNGS DEEQCQEGVP CGTFTFQCED RSCVKKPNPQ CDGRPDCRDG SDEEHCDCGL QGPSSRIVGG AVSSEGEWPW QASLQVRGRH ICGGALIADR WVITAAHCFQ EDSMASTVLW TVFLGKVWQN SRWPGEVSFK VSRLLLHPYH EEDSHDYDVA LLQLDHPVVR SAAVRPVCLP ARSHFFEPGL HCWITGWGAL REGGPISNAL QKVDVQLIPQ DLCSEVYRYQ VTPRMLCAGY RKGKKDACQG DSGGPLVCKA LSGRWFLAGL VSWGLGCGRP NYFGVYTRIT GVISWIQQVV T //