TMPS6_HUMAN
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 03-AUG-2022, entry version 174.
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}.
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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; CCDS13941.1; -. [Q8IU80-1]
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; 1.
DR IntAct; Q8IU80; 5.
DR STRING; 9606.ENSP00000371211; -.
DR BindingDB; Q8IU80; -.
DR ChEMBL; CHEMBL1795139; -.
DR GuidetoPHARMACOLOGY; 2422; -.
DR MEROPS; S01.308; -.
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; Q8IU80; -.
DR PeptideAtlas; Q8IU80; -.
DR PRIDE; Q8IU80; -.
DR ProteomicsDB; 70516; -. [Q8IU80-4]
DR ProteomicsDB; 70517; -. [Q8IU80-1]
DR ProteomicsDB; 70518; -. [Q8IU80-2]
DR ProteomicsDB; 70519; -. [Q8IU80-5]
DR Antibodypedia; 25860; 160 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 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; QVHYSIF; -.
DR OrthoDB; 1314811at2759; -.
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; 12 hits in 1067 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 117 other tissues.
DR ExpressionAtlas; Q8IU80; baseline and differential.
DR Genevisible; Q8IU80; HS.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0006879; P:cellular iron ion homeostasis; ISS:BHF-UCL.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0055072; P:iron ion homeostasis; IMP:UniProtKB.
DR GO; GO:0033619; P:membrane protein proteolysis; IMP:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
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; 2.40.10.10; -; 1.
DR Gene3D; 2.60.120.290; -; 1.
DR Gene3D; 3.30.70.960; -; 1.
DR Gene3D; 4.10.400.10; -; 3.
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 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; SSF49854; SSF49854; 2.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57424; SSF57424; 3.
DR SUPFAM; SSF82671; SSF82671; 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.
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
