UROM_HUMAN
ID UROM_HUMAN Reviewed; 640 AA.
AC P07911; B3KP48; B3KRN9; E9PEA4; Q540J6; Q6ZS84; Q8IYG0;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1988, sequence version 1.
DT 03-AUG-2022, entry version 209.
DE RecName: Full=Uromodulin;
DE AltName: Full=Tamm-Horsfall urinary glycoprotein;
DE Short=THP;
DE Contains:
DE RecName: Full=Uromodulin, secreted form;
DE Flags: Precursor;
GN Name=UMOD;
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] (ISOFORM 1), SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=3453112; DOI=10.1126/science.3453112;
RA Pennica D., Kohr W.J., Kuang W.-J., Glaister D., Aggarwal B.B., Chen E.Y.,
RA Goeddel D.V.;
RT "Identification of human uromodulin as the Tamm-Horsfall urinary
RT glycoprotein.";
RL Science 236:83-88(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, AND
RP FUNCTION.
RX PubMed=3498215; DOI=10.1126/science.3498215;
RA Hession C., Decker J.M., Sherblom A.P., Kumar S., Yue C.C.,
RA Mattaliano R.J., Tizard R., Kawashima E., Schmeissner U., Heletky S.,
RA Chow E.P., Burne C.A., Shaw A., Muchmore A.V.;
RT "Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines.";
RL Science 237:1479-1484(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ADTKD1 CYS-103; TYR-148 AND
RP ARG-217.
RX PubMed=12471200; DOI=10.1136/jmg.39.12.882;
RA Hart T.C., Gorry M.C., Hart P.S., Woodard A.S., Shihabi Z., Sandhu J.,
RA Shirts B., Xu L., Zhu H., Barmada M.M., Bleyer A.J.;
RT "Mutations of the UMOD gene are responsible for medullary cystic kidney
RT disease 2 and familial juvenile hyperuricaemic nephropathy.";
RL J. Med. Genet. 39:882-892(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 4 AND 5).
RC TISSUE=Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Kidney;
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 [7]
RP PROTEIN SEQUENCE OF 578-587, PROTEOLYTIC CLEAVAGE, IDENTIFICATION BY MASS
RP SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18375198; DOI=10.1016/j.bbrc.2008.03.099;
RA Santambrogio S., Cattaneo A., Bernascone I., Schwend T., Jovine L.,
RA Bachi A., Rampoldi L.;
RT "Urinary uromodulin carries an intact ZP domain generated by a conserved C-
RT terminal proteolytic cleavage.";
RL Biochem. Biophys. Res. Commun. 370:410-413(2008).
RN [8]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=7028707;
RA Sikri K.L., Foster C.L., MacHugh N., Marshall R.D.;
RT "Localization of Tamm-Horsfall glycoprotein in the human kidney using
RT immuno-fluorescence and immuno-electron microscopical techniques.";
RL J. Anat. 132:597-605(1981).
RN [9]
RP GPI-ANCHOR, AND SUBCELLULAR LOCATION.
RX PubMed=2249987; DOI=10.1016/s0021-9258(17)45284-7;
RA Rindler M.J., Naik S.S., Li N., Hoops T.C., Peraldi M.-N.;
RT "Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a
RT phosphatidylinositol-linked membrane protein.";
RL J. Biol. Chem. 265:20784-20789(1990).
RN [10]
RP SUBCELLULAR LOCATION, SUBUNIT, MUTAGENESIS OF ASP-430; LEU-435; VAL-458;
RP 586-ARG--SER-589; 598-VAL--ASN-600; 602-GLY-PRO-603 AND 605-THR--LYS-607,
RP REGION, AND GLYCOSYLATION.
RX PubMed=19005207; DOI=10.1091/mbc.e08-08-0876;
RA Schaeffer C., Santambrogio S., Perucca S., Casari G., Rampoldi L.;
RT "Analysis of uromodulin polymerization provides new insights into the
RT mechanisms regulating ZP domain-mediated protein assembly.";
RL Mol. Biol. Cell 20:589-599(2009).
RN [11]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20798515; DOI=10.1159/000320554;
RA Schmid M., Prajczer S., Gruber L.N., Bertocchi C., Gandini R., Pfaller W.,
RA Jennings P., Joannidis M.;
RT "Uromodulin facilitates neutrophil migration across renal epithelial
RT monolayers.";
RL Cell. Physiol. Biochem. 26:311-318(2010).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=20172860; DOI=10.1093/hmg/ddq077;
RA Zaucke F., Boehnlein J.M., Steffens S., Polishchuk R.S., Rampoldi L.,
RA Fischer A., Pasch A., Boehm C.W., Baasner A., Attanasio M., Hoppe B.,
RA Hopfer H., Beck B.B., Sayer J.A., Hildebrandt F., Wolf M.T.;
RT "Uromodulin is expressed in renal primary cilia and UMOD mutations result
RT in decreased ciliary uromodulin expression.";
RL Hum. Mol. Genet. 19:1985-1997(2010).
RN [13]
RP GLYCOSYLATION AT ASN-232; ASN-322 AND ASN-396, STRUCTURE OF CARBOHYDRATES,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.m111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of N- and
RT O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 11:1-17(2012).
RN [14]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN ADTKD1.
RX PubMed=22776760; DOI=10.1159/000339752;
RA Wei X., Xu R., Yang Z., Li Z., Liao Y., Johnson R.J., Yu X., Chen W.;
RT "Novel uromodulin mutation in familial juvenile hyperuricemic
RT nephropathy.";
RL Am. J. Nephrol. 36:114-120(2012).
RN [15]
RP SUBUNIT, ELECTRON MICROSCOPY, SUBCELLULAR LOCATION, GLYCOSYLATION,
RP MUTAGENESIS OF 586-ARG--SER-589, PROTEOLYTIC CLEAVAGE BY HPN, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=26673890; DOI=10.7554/elife.08887;
RA Brunati M., Perucca S., Han L., Cattaneo A., Consolato F., Andolfo A.,
RA Schaeffer C., Olinger E., Peng J., Santambrogio S., Perrier R., Li S.,
RA Bokhove M., Bachi A., Hummler E., Devuyst O., Wu Q., Jovine L.,
RA Rampoldi L.;
RT "The serine protease hepsin mediates urinary secretion and polymerisation
RT of Zona Pellucida domain protein uromodulin.";
RL Elife 4:0-0(2015).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 295-610, ELECTRON MICROSCOPY,
RP SUBUNIT, SUBCELLULAR LOCATION, DISULFIDE BOND, DOMAIN, GLYCOSYLATION AT
RP ASN-396, MUTAGENESIS OF LEU-333; ILE-421 AND 586-ARG--SER-589, AND REGION.
RX PubMed=26811476; DOI=10.1073/pnas.1519803113;
RA Bokhove M., Nishimura K., Brunati M., Han L., de Sanctis D., Rampoldi L.,
RA Jovine L.;
RT "A structured interdomain linker directs self-polymerization of human
RT uromodulin.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:1552-1557(2016).
RN [17] {ECO:0007744|PDB:6ZS5, ECO:0007744|PDB:6ZYA}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS), SUBUNIT, DOMAIN,
RP GLYCOSYLATION AT ASN-396 AND ASN-513, AND DISULFIDE BONDS.
RX PubMed=32815518; DOI=10.7554/elife.60265;
RA Stanisich J.J., Zyla D.S., Afanasyev P., Xu J., Kipp A., Olinger E.,
RA Devuyst O., Pilhofer M., Boehringer D., Glockshuber R.;
RT "The cryo-EM structure of the human uromodulin filament core reveals a
RT unique assembly mechanism.";
RL Elife 9:e60265-e60265(2020).
RN [18] {ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6TQL}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.35 ANGSTROMS) OF 25-587, SUBUNIT,
RP DOMAIN, GLYCOSYLATION AT ASN-322; ASN-396 AND ASN-513, DISULFIDE BONDS, AND
RP MUTAGENESIS OF ARG-415; 555-PHE-ALA-556 AND 586-ARG--SER-589.
RX PubMed=33196145; DOI=10.15252/embj.2020106807;
RA Stsiapanava A., Xu C., Brunati M., Zamora-Caballero S., Schaeffer C.,
RA Bokhove M., Han L., Hebert H., Carroni M., Yasumasu S., Rampoldi L., Wu B.,
RA Jovine L.;
RT "Cryo-EM structure of native human uromodulin, a zona pellucida module
RT polymer.";
RL EMBO J. 39:e106807-e106807(2020).
RN [19]
RP VARIANT ADTKD1 TYR-223.
RX PubMed=12900848; DOI=10.1016/s0272-6386(03)00670-x;
RA Bleyer A.J., Trachtman H., Sandhu J., Gorry M.C., Hart T.C.;
RT "Renal manifestations of a mutation in the uromodulin (Tamm Horsfall
RT protein) gene.";
RL Am. J. Kidney Dis. 42:E20-E26(2003).
RN [20]
RP INVOLVEMENT IN ADTKD1, VARIANTS ADTKD1 TRP-148; SER-150; ARG-315 AND
RP TYR-317, AND CHARACTERIZATION OF VARIANTS ADTKD1 TRP-148; SER-150; ARG-315
RP AND TYR-317.
RX PubMed=14570709; DOI=10.1093/hmg/ddg353;
RA Rampoldi L., Caridi G., Santon D., Boaretto F., Bernascone I., Lamorte G.,
RA Tardanico R., Dagnino M., Colussi G., Scolari F., Ghiggeri G.M.,
RA Amoroso A., Casari G.;
RT "Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export
RT dynamics.";
RL Hum. Mol. Genet. 12:3369-3384(2003).
RN [21]
RP INVOLVEMENT IN ADTKD1, AND VARIANTS ADTKD1 ALA-59; ARG-112; ARG-126;
RP TYR-170; SER-185; GLY-204; GLY-217; PRO-222; MET-225 AND ARG-282.
RX PubMed=14569098; DOI=10.1097/01.asn.0000092147.83480.b5;
RA Dahan K., Devuyst O., Smaers M., Vertommen D., Loute G., Poux J.M.,
RA Viron B., Jacquot C., Gagnadoux M.F., Chauveau D., Buchler M., Cochat P.,
RA Cosyns J.P., Mougenot B., Rider M.H., Antignac C., Verellen-Dumoulin C.,
RA Pirson Y.;
RT "A cluster of mutations in the UMOD gene causes familial juvenile
RT hyperuricemic nephropathy with abnormal expression of uromodulin.";
RL J. Am. Soc. Nephrol. 14:2883-2893(2003).
RN [22]
RP VARIANTS ADTKD1 TYR-77; ARG-126; SER-128; TYR-255 AND GLY-300.
RX PubMed=12629136; DOI=10.1210/jc.2002-021973;
RA Turner J.J.O., Stacey J.M., Harding B., Kotanko P., Lhotta K., Puig J.G.,
RA Roberts I., Torres R.J., Thakker R.V.;
RT "UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.";
RL J. Clin. Endocrinol. Metab. 88:1398-1401(2003).
RN [23]
RP VARIANTS ADTKD1 93-VAL--GLY-97 DELINS ALA-ALA-SER-CYS; LYS-225 AND TRP-248.
RX PubMed=14531790; DOI=10.1046/j.1523-1755.2003.00269.x;
RA Wolf M.T.F., Mucha B.E., Attanasio M., Zalewski I., Karle S.M.,
RA Neumann H.P.H., Rahman N., Bader B., Baldamus C.A., Otto E., Witzgall R.,
RA Fuchshuber A., Hildebrandt F.;
RT "Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon
RT 4, which encodes three EGF-like domains.";
RL Kidney Int. 64:1580-1587(2003).
RN [24]
RP INVOLVEMENT IN ADTKD1, AND VARIANTS ADTKD1 TRP-52; SER-135; PHE-195;
RP SER-202 AND LEU-236.
RX PubMed=15086896; DOI=10.1111/j.1523-1755.2004.00559.x;
RA Kudo E., Kamatani N., Tezuka O., Taniguchi A., Yamanaka H., Yabe S.,
RA Osabe D., Shinohara S., Nomura K., Segawa M., Miyamoto T., Moritani M.,
RA Kunika K., Itakura M.;
RT "Familial juvenile hyperuricemic nephropathy: detection of mutations in the
RT uromodulin gene in five Japanese families.";
RL Kidney Int. 65:1589-1597(2004).
RN [25]
RP VARIANT ADTKD1 GLY-347, AND CHARACTERIZATION OF VARIANT ADTKD1 GLY-347.
RX PubMed=15575003; DOI=10.1093/ndt/gfh524;
RA Tinschert S., Ruf N., Bernascone I., Sacherer K., Lamorte G.,
RA Neumayer H.H., Nurnberg P., Luft F.C., Rampoldi L.;
RT "Functional consequences of a novel uromodulin mutation in a family with
RT familial juvenile hyperuricaemic nephropathy.";
RL Nephrol. Dial. Transplant. 19:3150-3154(2004).
RN [26]
RP VARIANT ADTKD1 PRO-316.
RX PubMed=15983957; DOI=10.1053/j.ajkd.2005.04.003;
RA Lens X.M., Banet J.F., Outeda P., Barrio-Lucia V.;
RT "A novel pattern of mutation in uromodulin disorders: autosomal dominant
RT medullary cystic kidney disease type 2, familial juvenile hyperuricemic
RT nephropathy, and autosomal dominant glomerulocystic kidney disease.";
RL Am. J. Kidney Dis. 46:52-57(2005).
RN [27]
RP VARIANT ADTKD1 ARG-236, AND CHARACTERIZATION OF VARIANTS ADTKD1 ALA-59;
RP SER-128; TRP-148; SER-150; GLY-204; ARG-217; LYS-225; ARG-236 AND ARG-315.
RX PubMed=17010121; DOI=10.1111/j.1600-0854.2006.00481.x;
RA Bernascone I., Vavassori S., Di Pentima A., Santambrogio S., Lamorte G.,
RA Amoroso A., Scolari F., Ghiggeri G.M., Casari G., Polishchuk R.,
RA Rampoldi L.;
RT "Defective intracellular trafficking of uromodulin mutant isoforms.";
RL Traffic 7:1567-1579(2006).
RN [28]
RP VARIANT ADTKD1 GLU-461.
RX PubMed=21060763; DOI=10.3346/jkms.2010.25.11.1680;
RA Lee D.H., Kim J.K., Oh S.E., Noh J.W., Lee Y.K.;
RT "A case of familial juvenile hyperuricemic nephropathy with novel
RT uromodulin gene mutation, a novel heterozygous missense mutation in
RT Korea.";
RL J. Korean Med. Sci. 25:1680-1682(2010).
RN [29]
RP VARIANT ADTKD1 ARG-230.
RX PubMed=23197950; DOI=10.1159/000337343;
RA Nakayama M., Mori Y., Ota N., Ishida M., Shiotsu Y., Matsuoka E., Kado H.,
RA Ishida R., Nakata M., Kitani T., Tamagaki K., Sekita C., Taniguchi A.;
RT "A Japanese family suffering from familial juvenile hyperuricemic
RT nephropathy due to a rare mutation of the uromodulin gene.";
RL Case Rep. Nephrol. Urol. 2:15-19(2012).
RN [30]
RP VARIANTS ADTKD1 GLU-109; GLN-236 AND TRP-248, CHARACTERIZATION OF VARIANTS
RP ADTKD1 GLU-109; GLN-236 AND TRP-248, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=23988501; DOI=10.1016/j.gene.2013.08.041;
RA Liu M., Chen Y., Liang Y., Liu Y., Wang S., Hou P., Zhang H., Zhao M.;
RT "Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead
RT to abnormal uromodulin intracellular trafficking.";
RL Gene 531:363-369(2013).
RN [31]
RP VARIANT ARG-155, CHARACTERIZATION OF VARIANTS ADTKD1 93-VAL--GLY-97 DELINS
RP ALA-ALA-SER-CYS AND SER-150, AND CHARACTERIZATION OF VARIANT ARG-155.
RX PubMed=25436415; DOI=10.1016/j.febslet.2014.11.029;
RA Stewart A.P., Sandford R.N., Karet Frankl F.E., Edwardson J.M.;
RT "Pathogenic uromodulin mutations result in premature intracellular
RT polymerization.";
RL FEBS Lett. 589:89-93(2015).
RN [32]
RP VARIANT ADTKD1 GLY-120, AND CHARACTERIZATION OF VARIANT ADTKD1 GLY-120.
RX PubMed=27729211; DOI=10.1016/j.clinbiochem.2016.10.003;
RA Satanovskij R., Bader A., Block M., Herbst V., Schlumberger W., Haack T.,
RA Nockher W.A., Heemann U., Renders L., Schmaderer C., Angermann S., Wen M.,
RA Meitinger T., Scherberich J., Steubl D.;
RT "A new missense mutation in UMOD gene leads to severely reduced serum
RT uromodulin concentrations - A tool for the diagnosis of uromodulin-
RT associated kidney disease.";
RL Clin. Biochem. 50:155-158(2017).
CC -!- FUNCTION: [Uromodulin]: Functions in biogenesis and organization of the
CC apical membrane of epithelial cells of the thick ascending limb of
CC Henle's loop (TALH), where it promotes formation of complex filamentous
CC gel-like structure that may play a role in the water barrier
CC permeability (Probable). May serve as a receptor for binding and
CC endocytosis of cytokines (IL-1, IL-2) and TNF (PubMed:3498215).
CC Facilitates neutrophil migration across renal epithelia
CC (PubMed:20798515). {ECO:0000269|PubMed:20798515,
CC ECO:0000269|PubMed:3498215, ECO:0000305}.
CC -!- FUNCTION: [Uromodulin, secreted form]: In the urine, may contribute to
CC colloid osmotic pressure, retards passage of positively charged
CC electrolytes, prevents urinary tract infection and inhibits formation
CC of liquid containing supersaturated salts and subsequent formation of
CC salt crystals. {ECO:0000250|UniProtKB:Q91X17, ECO:0000305}.
CC -!- SUBUNIT: [Uromodulin, secreted form]: Homodimer that then polymerizes
CC into long filaments (PubMed:19005207, PubMed:26673890, PubMed:26811476,
CC PubMed:32815518, PubMed:33196145). The filaments can additionally
CC assemble laterally to form a sheet (PubMed:33196145).
CC {ECO:0000269|PubMed:19005207, ECO:0000269|PubMed:26673890,
CC ECO:0000269|PubMed:26811476, ECO:0000269|PubMed:32815518,
CC ECO:0000269|PubMed:33196145}.
CC -!- INTERACTION:
CC P07911; PRO_0000315044 [Q9BWP8]: COLEC11; NbExp=2; IntAct=EBI-2819647, EBI-26568155;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:22776760, ECO:0000269|PubMed:23988501,
CC ECO:0000269|PubMed:26673890, ECO:0000269|PubMed:7028707}; Lipid-anchor,
CC GPI-anchor {ECO:0000269|PubMed:2249987}. Basolateral cell membrane
CC {ECO:0000269|PubMed:7028707}; Lipid-anchor, GPI-anchor
CC {ECO:0000269|PubMed:2249987}. Cell projection, cilium membrane
CC {ECO:0000269|PubMed:20172860}. Note=Only a small fraction sorts to the
CC basolateral pole of tubular epithelial cells compared to apical
CC localization (PubMed:22776760). Secreted into urine after cleavage
CC (PubMed:18375198, PubMed:26811476). Colocalizes with NPHP1 and KIF3A
CC (PubMed:20172860). {ECO:0000269|PubMed:18375198,
CC ECO:0000269|PubMed:20172860, ECO:0000269|PubMed:26811476,
CC ECO:0000269|PubMed:3453112, ECO:0000269|PubMed:7028707}.
CC -!- SUBCELLULAR LOCATION: [Uromodulin, secreted form]: Secreted
CC {ECO:0000269|PubMed:18375198, ECO:0000269|PubMed:19005207,
CC ECO:0000269|PubMed:26673890, ECO:0000269|PubMed:26811476,
CC ECO:0000269|PubMed:3453112, ECO:0000269|PubMed:7028707}. Note=Detected
CC in urine. {ECO:0000269|PubMed:18375198, ECO:0000269|PubMed:26811476,
CC ECO:0000269|PubMed:3453112, ECO:0000269|PubMed:7028707}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P07911-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P07911-2; Sequence=VSP_017565;
CC Name=3;
CC IsoId=P07911-3; Sequence=VSP_017566;
CC Name=4;
CC IsoId=P07911-4; Sequence=VSP_040973;
CC Name=5;
CC IsoId=P07911-5; Sequence=VSP_054828;
CC -!- TISSUE SPECIFICITY: Expressed in the tubular cells of the kidney. Most
CC abundant protein in normal urine (at protein level). Synthesized
CC exclusively in the kidney. Expressed exclusively by epithelial cells of
CC the thick ascending limb of Henle's loop (TALH) and of distal
CC convoluted tubule lumen. {ECO:0000269|PubMed:18375198,
CC ECO:0000269|PubMed:22776760, ECO:0000269|PubMed:23988501,
CC ECO:0000269|PubMed:3453112, ECO:0000269|PubMed:7028707}.
CC -!- DOMAIN: The ZP domain mediates polymerization, leading to the formation
CC of long filaments. The core of the filament consists of stacked ZP
CC domains which assemble into a helical structure. Each ZP domain
CC consists of an N-terminal (ZP-N) and C-terminal (ZP-C) region connected
CC by a flexible linker; the linker allows the ZP domain to wrap around
CC the ZP-C subdomain of the preceding subunit. The heavily glycosylated
CC N-terminal part of the protein (containing several EGF-like domains)
CC forms branches which protrude from the core and may be involved in
CC pathogen capture. {ECO:0000269|PubMed:26811476,
CC ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145}.
CC -!- PTM: N-glycosylated (PubMed:19005207, PubMed:26673890, PubMed:26811476,
CC PubMed:32815518, PubMed:33196145). N-glycan heterogeneity at Asn-232:
CC Hex7HexNAc6 (major) and dHex1Hex7HexNAc6 (minor); at Asn-322:
CC dHex1Hex6HexNAc5 (minor), dHex1Hex7HexNAc6 (major) and dHex1Hex8HexNAc7
CC (minor); at Asn-396: Hex6HexNAc5 (major), dHex1Hex6HexNAc5 (minor) and
CC Hex7HexNAc6 (minor) (PubMed:22171320). {ECO:0000269|PubMed:19005207,
CC ECO:0000269|PubMed:22171320, ECO:0000269|PubMed:26673890,
CC ECO:0000269|PubMed:26811476, ECO:0000269|PubMed:32815518,
CC ECO:0000269|PubMed:33196145}.
CC -!- PTM: Proteolytically cleaved at a conserved C-terminal proteolytic
CC cleavage site to generate the secreted form found in urine
CC (PubMed:18375198, PubMed:19005207). This cleavage is catalyzed by HPN
CC (PubMed:26673890). {ECO:0000269|PubMed:18375198,
CC ECO:0000269|PubMed:19005207, ECO:0000269|PubMed:26673890}.
CC -!- DISEASE: Tubulointerstitial kidney disease, autosomal dominant, 1
CC (ADTKD1) [MIM:162000]: A form of autosomal dominant tubulointerstitial
CC kidney disease, a genetically heterogeneous disorder characterized by
CC slowly progressive loss of kidney function, bland urinary sediment,
CC hyperuricemia, absent or mildly increased albuminuria, lack of severe
CC hypertension during the early stages, and normal or small kidneys on
CC ultrasound. Renal histology shows variable abnormalities including
CC interstitial fibrosis with tubular atrophy, microcystic dilatation of
CC the tubules, thickening of tubular basement membranes, medullary cysts,
CC and secondary glomerulosclerotic or glomerulocystic changes with
CC abnormal glomerular tufting. There is significant variability, as well
CC as incomplete penetrance. {ECO:0000269|PubMed:12471200,
CC ECO:0000269|PubMed:12629136, ECO:0000269|PubMed:12900848,
CC ECO:0000269|PubMed:14531790, ECO:0000269|PubMed:14569098,
CC ECO:0000269|PubMed:14570709, ECO:0000269|PubMed:15086896,
CC ECO:0000269|PubMed:15575003, ECO:0000269|PubMed:15983957,
CC ECO:0000269|PubMed:17010121, ECO:0000269|PubMed:21060763,
CC ECO:0000269|PubMed:22776760, ECO:0000269|PubMed:23197950,
CC ECO:0000269|PubMed:23988501, ECO:0000269|PubMed:25436415,
CC ECO:0000269|PubMed:27729211}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC ---------------------------------------------------------------------------
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DR EMBL; M15881; AAA36798.1; -; mRNA.
DR EMBL; M17778; AAA36799.1; -; mRNA.
DR EMBL; AY162970; AAO64446.1; -; Genomic_DNA.
DR EMBL; AY162963; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AY162964; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AY162965; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AY162967; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AY162968; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AY162969; AAO64446.1; JOINED; Genomic_DNA.
DR EMBL; AK127643; BAC87070.1; -; mRNA.
DR EMBL; AK055722; BAG51560.1; -; mRNA.
DR EMBL; AK091961; BAG52451.1; -; mRNA.
DR EMBL; AC106796; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035975; AAH35975.1; -; mRNA.
DR CCDS; CCDS10583.1; -. [P07911-1]
DR CCDS; CCDS61876.1; -. [P07911-5]
DR PIR; A30452; A30452.
DR RefSeq; NP_001008390.1; NM_001008389.2. [P07911-1]
DR RefSeq; NP_001265543.1; NM_001278614.1. [P07911-5]
DR RefSeq; NP_003352.2; NM_003361.3. [P07911-1]
DR PDB; 4WRN; X-ray; 3.20 A; A/B=295-610.
DR PDB; 6TQK; EM; 3.35 A; A/B/C=25-587.
DR PDB; 6TQL; EM; 3.96 A; A/B/C=292-587.
DR PDB; 6ZS5; EM; 3.50 A; A/D=1-640.
DR PDB; 6ZYA; EM; 3.50 A; A=1-640.
DR PDB; 7PFP; EM; 6.10 A; A/B/C=1-640.
DR PDB; 7Q3N; EM; 7.40 A; U=25-587.
DR PDBsum; 4WRN; -.
DR PDBsum; 6TQK; -.
DR PDBsum; 6TQL; -.
DR PDBsum; 6ZS5; -.
DR PDBsum; 6ZYA; -.
DR PDBsum; 7PFP; -.
DR PDBsum; 7Q3N; -.
DR AlphaFoldDB; P07911; -.
DR SMR; P07911; -.
DR BioGRID; 113216; 4.
DR IntAct; P07911; 19.
DR STRING; 9606.ENSP00000379438; -.
DR GlyConnect; 613; 204 N-Linked glycans (5 sites), 20 O-Linked glycans (13 sites).
DR GlyGen; P07911; 16 sites, 230 N-linked glycans (8 sites), 8 O-linked glycans (7 sites).
DR iPTMnet; P07911; -.
DR PhosphoSitePlus; P07911; -.
DR BioMuta; UMOD; -.
DR DMDM; 137116; -.
DR jPOST; P07911; -.
DR MassIVE; P07911; -.
DR PaxDb; P07911; -.
DR PeptideAtlas; P07911; -.
DR PRIDE; P07911; -.
DR ProteomicsDB; 19844; -.
DR ProteomicsDB; 52038; -. [P07911-1]
DR ProteomicsDB; 52039; -. [P07911-2]
DR ProteomicsDB; 52040; -. [P07911-3]
DR ProteomicsDB; 52041; -. [P07911-4]
DR Antibodypedia; 4003; 568 antibodies from 38 providers.
DR DNASU; 7369; -.
DR Ensembl; ENST00000396134.6; ENSP00000379438.2; ENSG00000169344.16. [P07911-5]
DR Ensembl; ENST00000396138.9; ENSP00000379442.5; ENSG00000169344.16. [P07911-1]
DR Ensembl; ENST00000570689.5; ENSP00000460548.1; ENSG00000169344.16. [P07911-1]
DR GeneID; 7369; -.
DR KEGG; hsa:7369; -.
DR MANE-Select; ENST00000396138.9; ENSP00000379442.5; NM_003361.4; NP_003352.2.
DR UCSC; uc002dgz.5; human. [P07911-1]
DR CTD; 7369; -.
DR DisGeNET; 7369; -.
DR GeneCards; UMOD; -.
DR GeneReviews; UMOD; -.
DR HGNC; HGNC:12559; UMOD.
DR HPA; ENSG00000169344; Tissue enriched (kidney).
DR MalaCards; UMOD; -.
DR MIM; 162000; phenotype.
DR MIM; 191845; gene.
DR neXtProt; NX_P07911; -.
DR OpenTargets; ENSG00000169344; -.
DR Orphanet; 88950; UMOD-related autosomal dominant tubulointerstitial kidney disease.
DR PharmGKB; PA37199; -.
DR VEuPathDB; HostDB:ENSG00000169344; -.
DR eggNOG; ENOG502QT6B; Eukaryota.
DR GeneTree; ENSGT00940000156742; -.
DR HOGENOM; CLU_028679_1_0_1; -.
DR InParanoid; P07911; -.
DR OMA; LECGVND; -.
DR OrthoDB; 665331at2759; -.
DR PhylomeDB; P07911; -.
DR TreeFam; TF330284; -.
DR PathwayCommons; P07911; -.
DR Reactome; R-HSA-446203; Asparagine N-linked glycosylation.
DR SignaLink; P07911; -.
DR SIGNOR; P07911; -.
DR BioGRID-ORCS; 7369; 11 hits in 1069 CRISPR screens.
DR GeneWiki; Tamm%E2%80%93Horsfall_protein; -.
DR GenomeRNAi; 7369; -.
DR Pharos; P07911; Tbio.
DR PRO; PR:P07911; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P07911; protein.
DR Bgee; ENSG00000169344; Expressed in renal medulla and 87 other tissues.
DR ExpressionAtlas; P07911; baseline and differential.
DR Genevisible; P07911; HS.
DR GO; GO:0031225; C:anchored component of membrane; IDA:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0060170; C:ciliary membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0019898; C:extrinsic component of membrane; TAS:ProtInc.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005201; F:extracellular matrix structural constituent; IBA:GO_Central.
DR GO; GO:0019864; F:IgG binding; IDA:BHF-UCL.
DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0006914; P:autophagy; IEA:Ensembl.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0030644; P:cellular chloride ion homeostasis; IEA:Ensembl.
DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc.
DR GO; GO:0030643; P:cellular phosphate ion homeostasis; IEA:Ensembl.
DR GO; GO:0034620; P:cellular response to unfolded protein; IEA:Ensembl.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; IEA:Ensembl.
DR GO; GO:0061077; P:chaperone-mediated protein folding; IEA:Ensembl.
DR GO; GO:0046720; P:citric acid secretion; IEA:Ensembl.
DR GO; GO:0072044; P:collecting duct development; IEA:Ensembl.
DR GO; GO:0097709; P:connective tissue replacement; IEA:Ensembl.
DR GO; GO:0097273; P:creatinine homeostasis; IEA:Ensembl.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IEA:Ensembl.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IEA:Ensembl.
DR GO; GO:0003094; P:glomerular filtration; IEA:Ensembl.
DR GO; GO:0007157; P:heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; IDA:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0072051; P:juxtaglomerular apparatus development; IEA:Ensembl.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IDA:BHF-UCL.
DR GO; GO:0006629; P:lipid metabolic process; IEA:Ensembl.
DR GO; GO:0072218; P:metanephric ascending thin limb development; IEA:Ensembl.
DR GO; GO:0072221; P:metanephric distal convoluted tubule development; IEA:Ensembl.
DR GO; GO:0072233; P:metanephric thick ascending limb development; IEA:Ensembl.
DR GO; GO:0060073; P:micturition; IEA:Ensembl.
DR GO; GO:0033555; P:multicellular organismal response to stress; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:1990266; P:neutrophil migration; IDA:BHF-UCL.
DR GO; GO:0002251; P:organ or tissue specific immune response; IEA:Ensembl.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IEA:Ensembl.
DR GO; GO:0055075; P:potassium ion homeostasis; IEA:Ensembl.
DR GO; GO:0072665; P:protein localization to vacuole; IEA:Ensembl.
DR GO; GO:0044861; P:protein transport into plasma membrane raft; IEA:Ensembl.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:0051223; P:regulation of protein transport; IEA:Ensembl.
DR GO; GO:0035809; P:regulation of urine volume; IEA:Ensembl.
DR GO; GO:0070294; P:renal sodium ion absorption; IEA:Ensembl.
DR GO; GO:0097744; P:renal urate salt excretion; IEA:Ensembl.
DR GO; GO:0003091; P:renal water homeostasis; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009414; P:response to water deprivation; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0008380; P:RNA splicing; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IEA:Ensembl.
DR GO; GO:0015747; P:urate transport; IEA:Ensembl.
DR GO; GO:0071918; P:urea transmembrane transport; IEA:Ensembl.
DR Gene3D; 2.60.40.4100; -; 1.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR024731; EGF_dom.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR042235; ZP-C.
DR InterPro; IPR001507; ZP_dom.
DR InterPro; IPR017977; ZP_dom_CS.
DR Pfam; PF12947; EGF_3; 2.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF00100; Zona_pellucida; 1.
DR PRINTS; PR00023; ZPELLUCIDA.
DR SMART; SM00181; EGF; 3.
DR SMART; SM00179; EGF_CA; 2.
DR SMART; SM00241; ZP; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS00010; ASX_HYDROXYL; 2.
DR PROSITE; PS01186; EGF_2; 3.
DR PROSITE; PS50026; EGF_3; 3.
DR PROSITE; PS01187; EGF_CA; 2.
DR PROSITE; PS00682; ZP_1; 1.
DR PROSITE; PS51034; ZP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Ciliopathy; Cilium; Direct protein sequencing; Disease variant;
KW Disulfide bond; EGF-like domain; Glycoprotein; GPI-anchor; Lipoprotein;
KW Membrane; Nephronophthisis; Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1..24
FT CHAIN 25..614
FT /note="Uromodulin"
FT /id="PRO_0000041671"
FT CHAIN 25..587
FT /note="Uromodulin, secreted form"
FT /id="PRO_0000407909"
FT PROPEP 615..640
FT /note="Removed in mature form"
FT /evidence="ECO:0000255"
FT /id="PRO_0000041672"
FT DOMAIN 28..64
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 65..107
FT /note="EGF-like 2; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 108..149
FT /note="EGF-like 3; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 334..589
FT /note="ZP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00375"
FT REGION 334..429
FT /note="ZP-N"
FT /evidence="ECO:0000305|PubMed:26811476,
FT ECO:0000305|PubMed:32815518, ECO:0000305|PubMed:33196145"
FT REGION 430..453
FT /note="Flexible linker; important for secretion and
FT polymerization into filaments"
FT /evidence="ECO:0000269|PubMed:26811476"
FT REGION 454..464
FT /note="Internal hydrophobic patch (IHP)"
FT /evidence="ECO:0000305|PubMed:26811476,
FT ECO:0000305|PubMed:32815518, ECO:0000305|PubMed:33196145"
FT REGION 465..589
FT /note="ZP-C"
FT /evidence="ECO:0000305|PubMed:26811476,
FT ECO:0000305|PubMed:32815518, ECO:0000305|PubMed:33196145"
FT REGION 586..589
FT /note="Essential for cleavage by HPN"
FT /evidence="ECO:0000269|PubMed:19005207,
FT ECO:0000269|PubMed:26673890, ECO:0000269|PubMed:26811476"
FT REGION 598..607
FT /note="Regulates polymerization into filaments"
FT /evidence="ECO:0000269|PubMed:19005207"
FT SITE 587..588
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:18375198"
FT LIPID 614
FT /note="GPI-anchor amidated serine"
FT /evidence="ECO:0000255"
FT CARBOHYD 38
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 76
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 80
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 232
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:22171320,
FT ECO:0000269|PubMed:26811476"
FT CARBOHYD 275
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 322
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:22171320,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK,
FT ECO:0007744|PDB:6TQL"
FT CARBOHYD 396
FT /note="N-linked (GlcNAc...) (complex) asparagine"
FT /evidence="ECO:0000269|PubMed:22171320,
FT ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145,
FT ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6TQL,
FT ECO:0007744|PDB:6ZS5, ECO:0007744|PDB:6ZYA"
FT CARBOHYD 513
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:32815518,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK,
FT ECO:0007744|PDB:6TQL, ECO:0007744|PDB:6ZS5,
FT ECO:0007744|PDB:6ZYA"
FT DISULFID 32..41
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 35..50
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 52..63
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 69..83
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 77..92
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 94..106
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 112..126
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 120..135
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 137..148
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 297..306
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK"
FT DISULFID 300..315
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK"
FT DISULFID 317..347
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK"
FT DISULFID 335..425
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145,
FT ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6ZS5,
FT ECO:0007744|PDB:6ZYA"
FT DISULFID 366..389
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145,
FT ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6ZS5,
FT ECO:0007744|PDB:6ZYA"
FT DISULFID 506..566
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|PubMed:26811476, ECO:0000269|PubMed:32815518,
FT ECO:0000269|PubMed:33196145, ECO:0007744|PDB:6TQK,
FT ECO:0007744|PDB:6ZS5, ECO:0007744|PDB:6ZYA"
FT DISULFID 527..582
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145,
FT ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6ZYA"
FT DISULFID 571..578
FT /evidence="ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:32815518, ECO:0000269|PubMed:33196145,
FT ECO:0007744|PDB:6TQK, ECO:0007744|PDB:6ZS5,
FT ECO:0007744|PDB:6ZYA"
FT VAR_SEQ 29
FT /note="A -> ARTKYNCPARWSWRTPQRGGDTEQGPDEDFTSQG (in isoform
FT 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054828"
FT VAR_SEQ 67..199
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_017565"
FT VAR_SEQ 133..154
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040973"
FT VAR_SEQ 205..234
FT /note="FVGQGGARMAETCVPVLRCNTAAPMWLNGT -> P (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017566"
FT VARIANT 52
FT /note="C -> W (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:15086896"
FT /id="VAR_073052"
FT VARIANT 59
FT /note="D -> A (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER)"
FT /evidence="ECO:0000269|PubMed:14569098,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_073053"
FT VARIANT 77
FT /note="C -> Y (in ADTKD1; dbSNP:rs121917768)"
FT /evidence="ECO:0000269|PubMed:12629136"
FT /id="VAR_025950"
FT VARIANT 93..97
FT /note="VCPEG -> AASC (in ADTKD1; results in mutant
FT retention in the ER; results is abnormal intracellular
FT polymerization of the mutant protein)"
FT /evidence="ECO:0000269|PubMed:14531790,
FT ECO:0000269|PubMed:25436415"
FT /id="VAR_025951"
FT VARIANT 103
FT /note="G -> C (in ADTKD1; dbSNP:rs28934584)"
FT /evidence="ECO:0000269|PubMed:12471200"
FT /id="VAR_017666"
FT VARIANT 109
FT /note="V -> E (in ADTKD1; causes a delay in protein export
FT to the plasma membrane due to a longer retention time in
FT the ER; dbSNP:rs780462125)"
FT /evidence="ECO:0000269|PubMed:23988501"
FT /id="VAR_071398"
FT VARIANT 112
FT /note="C -> R (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073054"
FT VARIANT 120
FT /note="C -> G (in ADTKD1; serum levels severely reduced;
FT dbSNP:rs1555487621)"
FT /evidence="ECO:0000269|PubMed:27729211"
FT /id="VAR_077514"
FT VARIANT 126
FT /note="C -> R (in ADTKD1; dbSNP:rs121917769)"
FT /evidence="ECO:0000269|PubMed:12629136,
FT ECO:0000269|PubMed:14569098"
FT /id="VAR_025952"
FT VARIANT 128
FT /note="N -> S (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER; dbSNP:rs121917770)"
FT /evidence="ECO:0000269|PubMed:12629136,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_025953"
FT VARIANT 135
FT /note="C -> S (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:15086896"
FT /id="VAR_073055"
FT VARIANT 148
FT /note="C -> W (in ADTKD1; phenotype overlapping with
FT medullary cystic kidney disease; causes a delay in protein
FT export to the plasma membrane due to a longer retention
FT time in the ER)"
FT /evidence="ECO:0000269|PubMed:14570709,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_025954"
FT VARIANT 148
FT /note="C -> Y (in ADTKD1; dbSNP:rs28934582)"
FT /evidence="ECO:0000269|PubMed:12471200"
FT /id="VAR_017667"
FT VARIANT 150
FT /note="C -> S (in ADTKD1; phenotype overlapping with
FT medullary cystic kidney disease; causes a delay in protein
FT export to the plasma membrane due to a longer retention
FT time in the ER; results is abnormal intracellular
FT polymerization of the mutant protein)"
FT /evidence="ECO:0000269|PubMed:14570709,
FT ECO:0000269|PubMed:17010121, ECO:0000269|PubMed:25436415"
FT /id="VAR_025955"
FT VARIANT 155
FT /note="C -> R (probable-disease association mutation found
FT in a patient with cystic kidney disease; results in mutant
FT retention in the ER; results is abnormal intracellular
FT polymerization of the mutant protein)"
FT /evidence="ECO:0000269|PubMed:25436415"
FT /id="VAR_073056"
FT VARIANT 170
FT /note="C -> Y (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073057"
FT VARIANT 185
FT /note="R -> S (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073058"
FT VARIANT 195
FT /note="C -> F (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:15086896"
FT /id="VAR_073059"
FT VARIANT 202
FT /note="W -> S (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:15086896"
FT /id="VAR_073060"
FT VARIANT 204
FT /note="R -> G (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER)"
FT /evidence="ECO:0000269|PubMed:14569098,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_073061"
FT VARIANT 217
FT /note="C -> G (in ADTKD1; dbSNP:rs28934583)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073062"
FT VARIANT 217
FT /note="C -> R (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER; dbSNP:rs28934583)"
FT /evidence="ECO:0000269|PubMed:12471200,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_017668"
FT VARIANT 222
FT /note="R -> P (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073063"
FT VARIANT 223
FT /note="C -> Y (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:12900848"
FT /id="VAR_025956"
FT VARIANT 225
FT /note="T -> K (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER)"
FT /evidence="ECO:0000269|PubMed:14531790,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_025957"
FT VARIANT 225
FT /note="T -> M (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073064"
FT VARIANT 230
FT /note="W -> R (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:23197950"
FT /id="VAR_071399"
FT VARIANT 236
FT /note="P -> L (in ADTKD1; dbSNP:rs1447458978)"
FT /evidence="ECO:0000269|PubMed:15086896"
FT /id="VAR_073065"
FT VARIANT 236
FT /note="P -> Q (in ADTKD1; causes a delay in protein export
FT to the plasma membrane due to a longer retention time in
FT the ER)"
FT /evidence="ECO:0000269|PubMed:23988501"
FT /id="VAR_071400"
FT VARIANT 236
FT /note="P -> R (in ADTKD1; results in defective trafficking
FT of mutant protein to the plasma membrane; the mutant is
FT retained in the ER)"
FT /evidence="ECO:0000269|PubMed:17010121"
FT /id="VAR_073066"
FT VARIANT 248
FT /note="C -> W (in ADTKD1; causes a delay in protein export
FT to the plasma membrane due to a longer retention time in
FT the ER; dbSNP:rs886043751)"
FT /evidence="ECO:0000269|PubMed:14531790,
FT ECO:0000269|PubMed:23988501"
FT /id="VAR_025958"
FT VARIANT 255
FT /note="C -> Y (in ADTKD1; dbSNP:rs121917771)"
FT /evidence="ECO:0000269|PubMed:12629136"
FT /id="VAR_025959"
FT VARIANT 282
FT /note="C -> R (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:14569098"
FT /id="VAR_073067"
FT VARIANT 300
FT /note="C -> G (in ADTKD1; dbSNP:rs121917772)"
FT /evidence="ECO:0000269|PubMed:12629136"
FT /id="VAR_025960"
FT VARIANT 315
FT /note="C -> R (in ADTKD1; causes a delay in protein export
FT to the plasma membrane due to a longer retention time in
FT the ER; dbSNP:rs121917773)"
FT /evidence="ECO:0000269|PubMed:14570709,
FT ECO:0000269|PubMed:17010121"
FT /id="VAR_025961"
FT VARIANT 316
FT /note="Q -> P (in ADTKD1; dbSNP:rs1555487318)"
FT /evidence="ECO:0000269|PubMed:15983957"
FT /id="VAR_073068"
FT VARIANT 317
FT /note="C -> Y (in ADTKD1; phenotype overlapping with
FT medullary cystic kidney disease; causes a delay in protein
FT export to the plasma membrane due to a longer retention
FT time in the ER)"
FT /evidence="ECO:0000269|PubMed:14570709"
FT /id="VAR_025962"
FT VARIANT 347
FT /note="C -> G (in ADTKD1; causes a delay in protein export
FT to the plasma membrane due to a longer retention time in
FT the ER)"
FT /evidence="ECO:0000269|PubMed:15575003"
FT /id="VAR_073069"
FT VARIANT 458
FT /note="V -> L (in dbSNP:rs55772253)"
FT /id="VAR_061993"
FT VARIANT 461
FT /note="A -> E (in ADTKD1)"
FT /evidence="ECO:0000269|PubMed:21060763"
FT /id="VAR_071401"
FT MUTAGEN 333
FT /note="L->K: Abolishes polymerization and filament
FT formation of the secreted form."
FT /evidence="ECO:0000269|PubMed:26811476"
FT MUTAGEN 415
FT /note="R->A: Abolishes polymerization. No effect on protein
FT trafficking or secretion. Suppresses the dominant-negative
FT loss of polymerization in 555-F-A-556 DEL or 586-A--A-589;
FT when associated with 555-F-A-556 DEL or 586-A--A-589."
FT /evidence="ECO:0000269|PubMed:33196145"
FT MUTAGEN 421
FT /note="I->K: Abolishes polymerization and filament
FT formation of the secreted form."
FT /evidence="ECO:0000269|PubMed:26811476"
FT MUTAGEN 430
FT /note="D->L: Impairs polymerization and filament formation
FT of the secreted form."
FT /evidence="ECO:0000269|PubMed:19005207"
FT MUTAGEN 435
FT /note="L->S: Impairs polymerization and filament formation
FT of the secreted form."
FT /evidence="ECO:0000269|PubMed:19005207"
FT MUTAGEN 458
FT /note="V->R: Leads to retention in the endoplasmic
FT reticulum, probably due to misfolding."
FT /evidence="ECO:0000269|PubMed:19005207"
FT MUTAGEN 555..556
FT /note="Missing: Abolishes polymerization, in a dominant-
FT negative manner. No effect on protein trafficking or
FT secretion. Suppresses the dominant-negative loss of
FT polymerization; when associated with A-415."
FT /evidence="ECO:0000269|PubMed:33196145"
FT MUTAGEN 586..589
FT /note="RFRS->AAAA: Abolishes cleavage by HPN. Abolishes
FT polymerization, in a dominant-negative manner. Suppresses
FT the dominant-negative loss of polymerization; when
FT associated with A-415."
FT /evidence="ECO:0000269|PubMed:19005207,
FT ECO:0000269|PubMed:26673890, ECO:0000269|PubMed:26811476,
FT ECO:0000269|PubMed:33196145"
FT MUTAGEN 598..600
FT /note="VLN->AAA: Decreased export from the endoplasmic
FT reticulum, leading to decreased secretion. Impairs
FT polymerization."
FT /evidence="ECO:0000269|PubMed:19005207"
FT MUTAGEN 602..603
FT /note="GP->AA: Decreased export from the endoplasmic
FT reticulum, leading to decreased secretion. Impairs
FT polymerization."
FT /evidence="ECO:0000269|PubMed:19005207"
FT MUTAGEN 605..607
FT /note="TRK->AAA: No effect on secretion. Does not impair
FT polymerization."
FT /evidence="ECO:0000269|PubMed:19005207"
FT CONFLICT 288
FT /note="T -> A (in Ref. 4; BAG51560)"
FT /evidence="ECO:0000305"
FT CONFLICT 503
FT /note="M -> I (in Ref. 4; BAG51560)"
FT /evidence="ECO:0000305"
FT CONFLICT 565
FT /note="H -> D (in Ref. 2; AAA36799)"
FT /evidence="ECO:0000305"
FT STRAND 294..296
FT /evidence="ECO:0007829|PDB:6TQK"
FT HELIX 297..299
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 302..309
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 312..316
FT /evidence="ECO:0007829|PDB:6TQK"
FT HELIX 319..321
FT /evidence="ECO:0007829|PDB:6TQK"
FT HELIX 325..329
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 332..335
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 337..345
FT /evidence="ECO:0007829|PDB:6TQK"
FT HELIX 346..351
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 358..363
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 369..371
FT /evidence="ECO:0007829|PDB:6ZS5"
FT STRAND 372..374
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 377..387
FT /evidence="ECO:0007829|PDB:6TQK"
FT HELIX 388..390
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 392..394
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 397..413
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 418..434
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 437..442
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 447..453
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 459..465
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 474..480
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 483..490
FT /evidence="ECO:0007829|PDB:6TQK"
FT TURN 496..498
FT /evidence="ECO:0007829|PDB:6ZS5"
FT STRAND 499..512
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 520..524
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 525..528
FT /evidence="ECO:0007829|PDB:6ZYA"
FT STRAND 536..544
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 546..551
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 556..558
FT /evidence="ECO:0007829|PDB:6TQK"
FT STRAND 562..572
FT /evidence="ECO:0007829|PDB:6TQK"
FT TURN 573..575
FT /evidence="ECO:0007829|PDB:6TQK"
SQ SEQUENCE 640 AA; 69761 MW; D26A07A76353AE48 CRC64;
MGQPSLTWML MVVVASWFIT TAATDTSEAR WCSECHSNAT CTEDEAVTTC TCQEGFTGDG
LTCVDLDECA IPGAHNCSAN SSCVNTPGSF SCVCPEGFRL SPGLGCTDVD ECAEPGLSHC
HALATCVNVV GSYLCVCPAG YRGDGWHCEC SPGSCGPGLD CVPEGDALVC ADPCQAHRTL
DEYWRSTEYG EGYACDTDLR GWYRFVGQGG ARMAETCVPV LRCNTAAPMW LNGTHPSSDE
GIVSRKACAH WSGHCCLWDA SVQVKACAGG YYVYNLTAPP ECHLAYCTDP SSVEGTCEEC
SIDEDCKSNN GRWHCQCKQD FNITDISLLE HRLECGANDM KVSLGKCQLK SLGFDKVFMY
LSDSRCSGFN DRDNRDWVSV VTPARDGPCG TVLTRNETHA TYSNTLYLAD EIIIRDLNIK
INFACSYPLD MKVSLKTALQ PMVSALNIRV GGTGMFTVRM ALFQTPSYTQ PYQGSSVTLS
TEAFLYVGTM LDGGDLSRFA LLMTNCYATP SSNATDPLKY FIIQDRCPHT RDSTIQVVEN
GESSQGRFSV QMFRFAGNYD LVYLHCEVYL CDTMNEKCKP TCSGTRFRSG SVIDQSRVLN
LGPITRKGVQ ATVSRAFSSL GLLKVWLPLL LSATLTLTFQ
