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UniProtKB/Swiss-Prot entry Q8WZ42


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Entry information
Entry name TITIN_HUMAN
Primary accession number Q8WZ42
Secondary accession numbers Q10465 Q10466 Q15598 Q2XUS3 Q32Q60 Q4U1Z6 Q6NSG0 Q6PDB1 Q6PJP0 Q7KYM2 Q7KYN4 Q7KYN5 Q7LDM3 Q7Z2X3 Q8TCG8 Q8WZ51 Q8WZ52 Q8WZ53 Q8WZB3 Q92761 Q92762 Q9UD97 Q9UP84 Q9Y6L9
Integrated into Swiss-Prot on June 13, 2006
Sequence was last modified on June 13, 2006 (Sequence version 2)
Annotations were last modified on    July 22, 2008 (Entry version 56)
Name and origin of the protein
Protein name Titin
Synonyms EC 2.7.11.1
Connectin
Rhabdomyosarcoma antigen MU-RMS-40.14
Gene name
Name: TTN
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE [MRNA] OF 3336-12202 (ISOFORM 4), AND VARIANTS ILE-498; GLU-1201; ARG-1572; MET-2610; SER-2831; MET-3261; HIS-12383; GLU-12679; ILE-19762; ILE-20718; ASN-23807; MET-24980 AND THR-27755.
TISSUE=Skeletal muscle;
PubMed=7569978 [NCBI, ExPASy, EBI, Israel, Japan]
Labeit S., Kolmerer B.;
"Titins, giant proteins in charge of muscle ultrastructure and elasticity.";
Science 270:293-296(1995).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND VARIANTS PRO-4215 AND PHE-4283.
PubMed=10850961 [NCBI, ExPASy, EBI, Israel, Japan]
Freiburg A., Trombitas K., Hell W., Cazorla O., Fougerousse F., Centner T., Kolmerer B., Witt C., Beckmann J.S., Gregorio C.C., Granzier H., Labeit S.;
"Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity.";
Circ. Res. 86:1114-1121(2000).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, TISSUE SPECIFICITY, INTERACTION WITH OBSCN, AND VARIANTS PRO-4215 AND PHE-4283.
PubMed=11717165 [NCBI, ExPASy, EBI, Israel, Japan]
Bang M.-L., Centner T., Fornoff F., Geach A.J., Gotthardt M., McNabb M., Witt C.C., Labeit D., Gregorio C.C., Granzier H., Labeit S.;
"The complete gene sequence of titin, expression of an unusual ~700 kDa titin isoform and its interaction with obscurin identify a novel Z-line to I-band linking system.";
Circ. Res. 89:1065-1072(2001).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
DOI=10.1038/nature03466; PubMed=15815621 [NCBI, ExPASy, EBI, Israel, Japan]
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2 and 4.";
Nature 434:724-731(2005).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-626 AND 34071-34350 (ISOFORM 3).
TISSUE=Muscle, and Skeletal muscle;
DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan]
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
NUCLEOTIDE SEQUENCE [MRNA] OF 405-709 (ISOFORMS 1 AND 2).
TISSUE=Heart muscle;
PubMed=8937992 [NCBI, ExPASy, EBI, Israel, Japan]
Gautel M., Goulding D., Bullard B., Weber K., Furst D.O.;
"The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers.";
J. Cell Sci. 109:2747-2754(1996).
[7]
NUCLEOTIDE SEQUENCE [MRNA] OF 2023-2060, AND TISSUE SPECIFICITY.
TISSUE=Heart muscle;
DOI=10.1021/bi00002a021; PubMed=7819249 [NCBI, ExPASy, EBI, Israel, Japan]
Musco G., Tziatzos C., Schuck P., Pastore A.;
"Dissecting titin into its structural motifs: identification of an alpha helix near the N-terminus.";
Biochemistry 34:553-561(1995).
[8]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 3455-4473, AND VARIANTS PRO-3491; PRO-4215 AND PHE-4283.
PubMed=10051295 [NCBI, ExPASy, EBI, Israel, Japan]
Siu B.L., Niimura H., Osborne J.A., Fatkin D., MacRae C., Solomon S., Benson D.W., Seidman J.G., Seidman C.E.;
"Familial dilated cardiomyopathy locus maps to chromosome 2q31.";
Circulation 99:1022-1026(1999).
[9]
NUCLEOTIDE SEQUENCE [MRNA] OF 9806-12017 (ISOFORM 5).
TISSUE=Heart ventricle;
DOI=10.1023/A:1023410523184; PubMed=12785098 [NCBI, ExPASy, EBI, Israel, Japan]
Greaser M.L., Berri M., Warren C.M., Mozdziak P.E.;
"Species variations in cDNA sequence and exon splicing patterns in the extensible I-band region of cardiac titin: relation to passive tension.";
J. Muscle Res. Cell Motil. 23:473-482(2002).
[10]
NUCLEOTIDE SEQUENCE [MRNA] OF 12947-13797.
TISSUE=Embryonic rhabdomyosarcoma;
Behrends U., Gotz C., Mautner J.;
"Serological identification of rhabdomyosarcoma antigens.";
Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
[11]
NUCLEOTIDE SEQUENCE OF 14257-14543.
PubMed=8351016 [NCBI, ExPASy, EBI, Israel, Japan]
Gautel M., Lakey A., Barlow D.P., Holmes Z., Scales S., Leonard K., Labeit S., Mygland A., Gilhus N.E., Aarli J.A.;
"Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin.";
Neurology 43:1581-1585(1993).
[12]
NUCLEOTIDE SEQUENCE [MRNA] OF 21021-22120, AND NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 23754-24284.
PubMed=1582406 [NCBI, ExPASy, EBI, Israel, Japan]
Labeit S., Gautel M., Lakey A., Trinick J.;
"Towards a molecular understanding of titin.";
EMBO J. 11:1711-1716(1992).
[13]
NUCLEOTIDE SEQUENCE [MRNA] OF 29701-34350, AND PHOSPHORYLATION.
PubMed=8404852 [NCBI, ExPASy, EBI, Israel, Japan]
Gautel M., Leonard K., Labeit S.;
"Phosphorylation of KSF motifs in the C-terminal region of titin in differentiating myoblasts.";
EMBO J. 12:3827-3834(1993).
[14]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 33119-34350.
TISSUE=Skeletal muscle;
The German cDNA consortium;
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[15]
INTERACTION WITH TCAP.
DOI=10.1016/S0014-5793(98)00501-8; PubMed=9645487 [NCBI, ExPASy, EBI, Israel, Japan]
Mues A., van der Ven P.F.M., Young P., Furst D.O., Gautel M.;
"Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin.";
FEBS Lett. 428:111-114(1998).
[16]
INTERACTION WITH NEB.
DOI=10.1016/S0014-5793(02)03655-4; PubMed=12482578 [NCBI, ExPASy, EBI, Israel, Japan]
Ma K., Wang K.;
"Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications for the signaling and assembly role of titin and nebulin.";
FEBS Lett. 532:273-278(2002).
[17]
INTERACTION WITH FHL2.
DOI=10.1242/jcs.00181; PubMed=12432079 [NCBI, ExPASy, EBI, Israel, Japan]
Lange S., Auerbach D., McLoughlin P., Perriard E., Schafer B.W., Perriard J.-C., Ehler E.;
"Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2.";
J. Cell Sci. 115:4925-4936(2002).
[18]
INTERACTION WITH ANK1.
DOI=10.1074/jbc.M209012200; PubMed=12444090 [NCBI, ExPASy, EBI, Israel, Japan]
Kontrogianni-Konstantopoulos A., Bloch R.J.;
"The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin.";
J. Biol. Chem. 278:3985-3991(2003).
[19]
INTERACTION WITH ANKRD1; ANKRD2; ANKRD23 AND CAPN3.
DOI=10.1016/j.jmb.2003.09.012; PubMed=14583192 [NCBI, ExPASy, EBI, Israel, Japan]
Miller M.K., Bang M.-L., Witt C.C., Labeit D., Trombitas C., Watanabe K., Granzier H., McElhinny A.S., Gregorio C.C., Labeit S.;
"The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules.";
J. Mol. Biol. 333:951-964(2003).
[20]
INTERACTION WITH CRYAB.
DOI=10.1074/jbc.M307473200; PubMed=14676215 [NCBI, ExPASy, EBI, Israel, Japan]
Bullard B., Ferguson C., Minajeva A., Leake M.C., Gautel M., Labeit D., Ding L., Labeit S., Horwitz J., Leonard K.R., Linke W.A.;
"Association of the chaperone alphaB-crystallin with titin in heart muscle.";
J. Biol. Chem. 279:7917-7924(2004).
[21]
INTERACTION WITH TRIM63 AND TRIM55.
DOI=10.1016/j.jmb.2005.05.021; PubMed=15967462 [NCBI, ExPASy, EBI, Israel, Japan]
Witt S.H., Granzier H., Witt C.C., Labeit S.;
"MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination.";
J. Mol. Biol. 350:713-722(2005).
[22]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-8490, AND MASS SPECTROMETRY.
DOI=10.1038/sj.emboj.7601384; PubMed=17053785 [NCBI, ExPASy, EBI, Israel, Japan]
Wang Y., Du D., Fang L., Yang G., Zhang C., Zeng R., Ullrich A., Lottspeich F., Chen Z.;
"Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling.";
EMBO J. 25:5058-5070(2006).
[23]
INTERACTION WITH LAMIN, AND SUBCELLULAR LOCATION.
DOI=10.1242/jcs.02728; PubMed=16410549 [NCBI, ExPASy, EBI, Israel, Japan]
Zastrow M.S., Flaherty D.B., Benian G.M., Wilson K.L.;
"Nuclear titin interacts with A- and B-type lamins in vitro and in vivo.";
J. Cell Sci. 119:239-249(2006).
[24]
REVIEW.
DOI=10.1152/ajpheart.00816.2005; PubMed=16537787 [NCBI, ExPASy, EBI, Israel, Japan]
Hoshijima M.;
"Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures.";
Am. J. Physiol. 290:H1313-H1325(2006).
[25]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33938 AND SER-33942, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-5304 AND SER-5306 (ISOFORM 6), AND MASS SPECTROMETRY.
TISSUE=Epithelium;
DOI=10.1021/pr070152u; PubMed=17924679 [NCBI, ExPASy, EBI, Israel, Japan]
Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra.";
J. Proteome Res. 6:4150-4162(2007).
[26]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22525 AND SER-22534, AND MASS SPECTROMETRY.
DOI=10.1073/pnas.0611217104; PubMed=17287340 [NCBI, ExPASy, EBI, Israel, Japan]
Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A.;
"Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry.";
Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007).
[27]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-9203 AND THR-9207, AND MASS SPECTROMETRY.
DOI=10.1126/science.1140321; PubMed=17525332 [NCBI, ExPASy, EBI, Israel, Japan]
Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.";
Science 316:1160-1166(2007).
[28]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-4065 AND SER-4068, AND MASS SPECTROMETRY.
DOI=10.2116/analsci.24.161; PubMed=18187866 [NCBI, ExPASy, EBI, Israel, Japan]
Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y.;
"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column.";
Anal. Sci. 24:161-166(2008).
[29]
STRUCTURE BY NMR OF 33483-33579.
DOI=10.1016/S0969-2126(01)00170-8; PubMed=7613868 [NCBI, ExPASy, EBI, Israel, Japan]
Pfuhl M., Pastore A.;
"Tertiary structure of an immunoglobulin-like domain from the giant muscle protein titin: a new member of the I set.";
Structure 3:391-401(1995).
[30]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 32172-32489, FUNCTION, ENZYME REGULATION, INTERACTION WITH CALM, PHOSPHORYLATION AT TYR-32341, AND MUTAGENESIS OF LYS-32207 AND TYR-32341.
DOI=10.1038/27603; PubMed=9804419 [NCBI, ExPASy, EBI, Israel, Japan]
Mayans O., van der Ven P.F.M., Wilm M., Mues A., Young P., Furst D.O., Wilmanns M., Gautel M.;
"Structural basis for activation of the titin kinase domain during myofibrillogenesis.";
Nature 395:863-869(1998).
[31]
STRUCTURE BY NMR OF 22283-22385.
DOI=10.1016/S0969-2126(98)00129-4; PubMed=9782056 [NCBI, ExPASy, EBI, Israel, Japan]
Goll C.M., Pastore A., Nilges M.;
"The three-dimensional structure of a type I module from titin: a prototype of intracellular fibronectin type III domains.";
Structure 6:1291-1302(1998).
[32]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 2073-2171, AND DISULFIDE BOND.
DOI=10.1016/S0969-2126(01)00591-3; PubMed=11525170 [NCBI, ExPASy, EBI, Israel, Japan]
Mayans O., Wuerges J., Canela S., Gautel M., Wilmanns M.;
"Structural evidence for a possible role of reversible disulphide bridge formation in the elasticity of the muscle protein titin.";
Structure 9:331-340(2001).
[33]
X-RAY CRYSTALLOGRAPHY (2.44 ANGSTROMS) OF 1-196 IN COMPLEX WITH TCAP.
DOI=10.1038/nature04343; PubMed=16407954 [NCBI, ExPASy, EBI, Israel, Japan]
Zou P., Pinotsis N., Lange S., Song Y.-H., Popov A., Mavridis I., Mayans O.M., Gautel M., Wilmanns M.;
"Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk.";
Nature 439:229-233(2006).
[34]
VARIANT CMH9 LEU-740.
DOI=10.1006/bbrc.1999.1221; PubMed=10462489 [NCBI, ExPASy, EBI, Israel, Japan]
Satoh M., Takahashi M., Sakamoto T., Hiroe M., Marumo F., Kimura A.;
"Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene.";
Biochem. Biophys. Res. Commun. 262:411-417(1999).
[35]
INVOLVEMENT IN LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2J, AND VARIANT TMD PRO-34315.
DOI=10.1086/342380; PubMed=12145747 [NCBI, ExPASy, EBI, Israel, Japan]
Hackman P., Vihola A., Haravuori H., Marchand S., Sarparanta J., De Seze J., Labeit S., Witt C., Peltonen L., Richard I., Udd B.;
"Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.";
Am. J. Hum. Genet. 71:492-500(2002).
[36]
VARIANTS CMD1G MET-54; VAL-743; TYR-3799 AND ASN-4465, VARIANTS CYS-328; GLN-4084 AND PRO-4215, AND CHARACTERIZATION OF VARIANTS CMD1G MET-54 AND VAL-743.
DOI=10.1006/bbrc.2002.6448; PubMed=11846417 [NCBI, ExPASy, EBI, Israel, Japan]
Itoh-Satoh M., Hayashi T., Nishi H., Koga Y., Arimura T., Koyanagi T., Takahashi M., Hohda S., Ueda K., Nouchi T., Hiroe M., Marumo F., Imaizumi T., Yasunami M., Kimura A.;
"Titin mutations as the molecular basis for dilated cardiomyopathy.";
Biochem. Biophys. Res. Commun. 291:385-393(2002).
[37]
VARIANT CMD1G ARG-976.
DOI=10.1038/ng815; PubMed=11788824 [NCBI, ExPASy, EBI, Israel, Japan]
Gerull B., Gramlich M., Atherton J., McNabb M., Trombitas K., Sasse-Klaassen S., Seidman J.G., Seidman C., Granzier H., Labeit S., Frenneaux M., Thierfelder L.;
"Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy.";
Nat. Genet. 30:201-204(2002).
[38]
VARIANT TMD ASN-34306.
DOI=10.1002/ana.10647; PubMed=12891679 [NCBI, ExPASy, EBI, Israel, Japan]
Van den Bergh P.Y.K., Bouquiaux O., Verellen C., Marchand S., Richard I., Hackman P., Udd B.;
"Tibial muscular dystrophy in a Belgian family.";
Ann. Neurol. 54:248-251(2003).
[39]
VARIANT CMD1G GLN-32996.
DOI=10.1007/s10974-005-9018-5; PubMed=16465475 [NCBI, ExPASy, EBI, Israel, Japan]
Matsumoto Y., Hayashi T., Inagaki N., Takahashi M., Hiroi S., Nakamura T., Arimura T., Nakamura K., Ashizawa N., Yasunami M., Ohe T., Yano K., Kimura A.;
"Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy.";
J. Muscle Res. Cell Motil. 26:367-374(2005).
[40]
VARIANT HMERF TRP-279, CHARACTERIZATION OF VARIANT HMERF TRP-279, AND INTERACTION WITH NBR1.
DOI=10.1126/science.1110463; PubMed=15802564 [NCBI, ExPASy, EBI, Israel, Japan]
Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., Udd B., Gautel M.;
"The kinase domain of titin controls muscle gene expression and protein turnover.";
Science 308:1599-1603(2005).
[41]
INVOLVEMENT IN EOMFC.
DOI=10.1002/ana.21089; PubMed=17444505 [NCBI, ExPASy, EBI, Israel, Japan]
Carmignac V., Salih M.A.M., Quijano-Roy S., Marchand S., Al Rayess M.M., Mukhtar M.M., Urtizberea J.A., Labeit S., Guicheney P., Leturcq F., Gautel M., Fardeau M., Campbell K.P., Richard I., Estournet B., Ferreiro A.;
"C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy.";
Ann. Neurol. 61:340-351(2007).
[42]
VARIANTS [LARGE SCALE ANALYSIS] TYR-60; MET-115; CYS-328; THR-360; ILE-498; MET-799; ILE-811; HIS-922; ASP-937; THR-1081; ARG-1137; GLU-1201; ALA-1202; SER-1295; ASP-1345; THR-1347; HIS-1350; LEU-1353; VAL-1393; CYS-1416; PRO-1441; VAL-1544; ARG-1572; GLY-1658; GLN-1664; ASP-1692; LEU-1744; GLY-1772; ILE-1907; HIS-1998; LEU-2107; THR-2118; THR-2164; TYR-2240; SER-2392; PHE-2432; MET-2610; MET-2771; PHE-2823; SER-2831; ILE-2930; ARG-3154; GLU-3191; LEU-3238; GLY-3250; MET-3261; GLN-3367; LYS-3482; PRO-3491; LYS-3570; VAL-3590; VAL-3762; PHE-3877; LEU-3965; PRO-4215; TRP-4238; PHE-4283; THR-4291; ASP-4303; GLU-4427; GLU-12310; HIS-12383; ALA-12469; CYS-12642; LYS-12657; GLU-12679; PHE-12720; CYS-12798; GLY-13049; LYS-13083; LEU-13096; ARG-13099; ALA-13297; MET-13399; THR-13418; VAL-13428; THR-13430; LYS-13434; ASN-13469; ASN-13495; SER-13785; HIS-13870; ILE-14109; GLN-14131; THR-14208; VAL-14728; THR-14999; THR-15021; VAL-15520; ILE-15555; GLN-15620; ILE-15629; CYS-15635; GLN-15700; PRO-15705; MET-15837; HIS-16058; ILE-16067; THR-16090; HIS-16195; CYS-16409; PRO-16424; MET-16629; ARG-16877; ASP-17060; VAL-17637; HIS-17838; ASN-17866; GLU-17906; ALA-18094; SER-18109; THR-18164; LEU-18221; THR-18222; GLN-18726; ALA-18835; LYS-18881; SER-18939; GLN-19000; GLN-19060; LYS-19091; SER-19224; ILE-19367; LYS-19392; SER-19480; GLY-19495; HIS-19665; ILE-19762; ARG-19947; MET-19956; GLN-19992; CYS-20057; LEU-20075; LYS-20179; THR-20198; VAL-20198; HIS-20331; THR-20408; LYS-20564; ILE-20718; PRO-20726; ASN-20892; ARG-20894; GLU-21125; SER-21403; CYS-21730; GLN-21747; ARG-21851; ARG-21851; ARG-21925; HIS-21995; VAL-22045; HIS-22149; ILE-22160; THR-22261; ASN-22306; HIS-22357; PRO-22408; HIS-22537; LEU-22584; PRO-22646; ALA-22670; ASP-22770; THR-22801; TRP-22823; GLN-22968; LEU-23074; PHE-23079; ASN-23282; TYR-23303; CYS-23306; SER-23515; GLN-23551; ASN-23807; ASN-23872; ALA-23891; HIS-23933; MET-23939; LEU-23952; GLY-24098; SER-24119; ILE-24133; ALA-24159; ALA-24239; LYS-24265; THR-24584; THR-24781; HIS-24799; HIS-24954; MET-24980; HIS-25659; THR-25679; ALA-25720; LYS-25821; LYS-25859; LYS-25879; VAL-25923; ILE-26045; GLU-26059; VAL-26134; CYS-26477; TYR-26843; ARG-27346; CYS-27652; VAL-27728; LEU-27754; THR-27755; VAL-27929; LEU-28132; GLN-28168; HIS-28538; THR-28572; THR-28948; VAL-28986; GLU-28993; VAL-28998; MET-29070; VAL-29090; CYS-29419; PRO-29479; LEU-29880; GLU-29976; GLY-30042; CYS-30107; PHE-30125; PRO-30211; THR-30412; SER-30617; ILE-30674; ILE-30809; ILE-30818; LYS-30825; THR-30856; ASP-30887; SER-30887; HIS-30897; HIS-30907; HIS-30946; PHE-31081; CYS-31107; GLY-31124; SER-31156; THR-31246; HIS-31330; ARG-31690; GLN-31724; ILE-31725; SER-31732; ILE-31886; CYS-32097; ASN-32171; ILE-32248; HIS-32281; HIS-32323; TRP-32411; VAL-32558; VAL-32610; VAL-32637; ALA-32922; ARG-32943; HIS-32953; LEU-33213; CYS-33242; MET-33387; ASP-33419; MET-33536; GLN-33568; LYS-33616; LEU-33620; VAL-33886; THR-33899; PRO-33904; ILE-33955 AND ALA-34115.
DOI=10.1038/nature05610; PubMed=17344846 [NCBI, ExPASy, EBI, Israel, Japan]
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
Comments
  • FUNCTION: Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.
  • CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
  • COFACTOR: Magnesium.
  • ENZYME REGULATION: Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase.
  • SUBUNIT: Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN (By similarity). Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 8 interacts with OBSCN isoform 3.
  • INTERACTION:
    P35609:ACTN2; NbExp=5; IntAct=EBI-681210, EBI-77797;
    Q5VST9:OBSCN; NbExp=3; IntAct=EBI-681210, EBI-941850;
    O15273:TCAP; NbExp=1; IntAct=EBI-681210, EBI-954089;
  • SUBCELLULAR LOCATION: Cytoplasm (Probable). Nucleus.
  • ALTERNATIVE PRODUCTS: 8 named isoforms [FASTA] produced by alternative splicing. A number of isoforms may be produced, ranging from 27000 to 33000 residues in different striated muscle tissues, the size of the full length protein may be up to 38138 residues.
    Name1
    Isoform IDQ8WZ42-1
    Note: No experimental confirmation available.
    This is the isoform sequence displayed in this entry.
    Name2
    Isoform IDQ8WZ42-2
    Note: No experimental confirmation available.
    Features which should be applied to build the isoform sequence: VSP_019138.
    Name3
    SynonymsSmall cardiac N2-B
    Isoform IDQ8WZ42-3
    Features which should be applied to build the isoform sequence: VSP_019139, VSP_019145.
    Name4
    SynonymsSoleus
    Isoform IDQ8WZ42-4
    Note: No experimental confirmation available.
    Features which should be applied to build the isoform sequence: VSP_019142, VSP_019151.
    Name5
    Isoform IDQ8WZ42-5
    Note: No experimental confirmation available.
    Features which should be applied to build the isoform sequence: VSP_019147, VSP_019148, VSP_019149, VSP_019150, VSP_019152.
    Name6
    SynonymsSmall cardiac novex-3
    Isoform IDQ8WZ42-6
    Note: Phosphorylated on Thr-5304 and Ser-5306.
    Features which should be applied to build the isoform sequence: VSP_019143, VSP_019146.
    Name7
    SynonymsCardiac novex-2
    Isoform IDQ8WZ42-7
    Features which should be applied to build the isoform sequence: VSP_019141, VSP_019144.
    Name8
    SynonymsCardiac novex-1
    Isoform IDQ8WZ42-8
    Features which should be applied to build the isoform sequence: VSP_019140.
  • TISSUE SPECIFICITY: Isoform 3, isoform 7 and isoform 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in cardiac tissues.
  • DOMAIN: ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site.
  • DOMAIN: The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.
  • PTM: Autophosphorylated (By similarity). Phosphorylated upon DNA damage, probably by ATM or ATR.
  • DISEASE: Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement.
  • DISEASE: Defects in TTN are the cause of cardiomyopathy familial hypertrophic type 9 (CMH9) [MIM:188840]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.
  • DISEASE: Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:604145]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
  • DISEASE: Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:600334]; also known as Udd myopathy. TMD is an autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later.
  • DISEASE: Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:608807]. LGMD2J is an autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset.
  • DISEASE: Defects in TTN are the cause of early-onset myopathy with fatal cardiomyopathy (EOMFC) [MIM:611705]. Early-onset myopathies are inherited muscle disorders that manifest typically from birth or infancy with hypotonia, muscle weakness, and delayed motor development. EOMFC is a titinopathy that, in contrast with the previously described examples, involves both heart and skeletal muscle, has a congenital onset, and is purely recessive. This phenotype is due to homozygous out-of-frame TTN deletions, which lead to a total absence of titin's C-terminal end from striated muscles and to secondary CAPN3 depletion.
  • MISCELLANEOUS: In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.
  • SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.
  • SIMILARITY: Contains 132 fibronectin type-III domains.
  • SIMILARITY: Contains 152 Ig-like (immunoglobulin-like) domains.
  • SIMILARITY: Contains 19 Kelch repeats.
  • SIMILARITY: Contains 1 protein kinase domain.
  • SIMILARITY: Contains 17 RCC1 repeats.
  • SIMILARITY: Contains 14 TPR repeats.
  • SIMILARITY: Contains 15 WD repeats.
  • SEQUENCE CAUTION:
    • Sequence=AAH58824.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 553
    • Sequence=AAH70170.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 627
  • WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=TTN";.
  • WEB RESOURCE: Name=Wikipedia; Note=Titin entry; URL="http://en.wikipedia.org/wiki/Titin";.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
X90568; CAA62188.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X90569; CAA62189.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ277892; CAD12455.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ277892; CAD12456.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ277892; CAD12457.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ277892; CAD12458.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ277892; CAD12459.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC013396; AAH13396.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC058824; AAH58824.1; ALT_SEQ; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC070170; AAH70170.1; ALT_SEQ; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC107797; AAI07798.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X98114; CAA66795.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X98115; CAA66796.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X83270; CAA58243.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF058332; AAD22603.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF058332; AAD22604.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF525413; AAP80791.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
DQ248309; ABB55264.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X64698; CAA45939.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X64699; CAA45940.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X64697; CAA45938.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X69490; CAA49245.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AL713647; CAD28458.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
PIR I38344; I38344.
I38346; I38346.
RefSeq NP_003310.3; -.
NP_596869.3; -.
NP_597676.2; -.
NP_597681.2; -.
UniGene Hs.654592
3D structure databases
PDB
1BPV; NMR; -; A=22283-22385.[ExPASy / RCSB / EBI]
1G1C; X-ray; 2.10 A; A/B=2073-2171.[ExPASy / RCSB / EBI]
1NCT; NMR; -; A=33483-33579.[ExPASy / RCSB / EBI]
1NCU; NMR; -; A=33483-33579.[ExPASy / RCSB / EBI]
1TIT; NMR; -; A=12677-12765.[ExPASy / RCSB / EBI]
1TIU; NMR; -; A=12677-12765.[ExPASy / RCSB / EBI]
1TKI; X-ray; 2.00 A; A/B=32172-32492.[ExPASy / RCSB / EBI]
1TNM; NMR; -; A=33489-33579.[ExPASy / RCSB / EBI]
1TNN; NMR; -; A=33489-33579.[ExPASy / RCSB / EBI]
1WAA; X-ray; 1.80 A; A/B/C/D/E/F=12677-12765.[ExPASy / RCSB / EBI]
1YA5; X-ray; 2.44 A; A/B=1-196.[ExPASy / RCSB / EBI]
2A38; X-ray; 2.00 A; A/B/C=1-194.[ExPASy / RCSB / EBI]
2BK8; X-ray; 1.69 A; A=32497-32590.[ExPASy / RCSB / EBI]
2F8V; X-ray; 2.75 A; A/B/C/D=1-196.[ExPASy / RCSB / EBI]
2ILL; X-ray; 2.20 A; A=31854-32047.[ExPASy / RCSB / EBI]
2J8H; X-ray; 1.99 A; A=31854-32047.[ExPASy / RCSB / EBI]
2J8O; X-ray; 2.49 A; A/B=31854-32047.[ExPASy / RCSB / EBI]
2NZI; X-ray; 2.90 A; A/B=31854-32155.[ExPASy / RCSB / EBI]
Detailed list of linked structures.
PDBsum 1BPV; -.
1G1C; -.
1NCT; -.
1NCU; -.
1TIT; -.
1TIU; -.
1TKI; -.
1TNM; -.
1TNN; -.
1WAA; -.
1YA5; -.
2A38; -.
2BK8; -.
2F8V; -.
2ILL; -.
2J8H; -.
2J8O; -.
2NZI; -.
ModBase Q8WZ42.
Protein-protein interaction databases
DIP DIP:29145N; -.
IntAct Q8WZ42; -.
PTM databases
PhosphoSite Q8WZ42; -.
Organism-specific databases
H-InvDB HIX0077703; -.
HGNC HGNC:12403; TTN.
GeneLynx TTN; Homo sapiens.
GenAtlas TTN.
HPA HPA007042; -.
MIM 188840; gene+phenotype. [NCBI / EBI]
600334; phenotype. [NCBI<