Description: Homo sapiens titin (TTN), transcript variant N2BA, mRNA. RefSeq Summary (NM_001256850): This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]. Transcript (Including UTRs) Position: hg19 chr2:179,390,717-179,672,150 Size: 281,434 Total Exon Count: 313 Strand: - Coding Region Position: hg19 chr2:179,391,739-179,669,369 Size: 277,631 Coding Exon Count: 312
ID:TITIN_HUMAN DESCRIPTION: RecName: Full=Titin; EC=2.7.11.1; AltName: Full=Connectin; AltName: Full=Rhabdomyosarcoma antigen MU-RMS-40.14; 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. Interacts with CMYA5. INTERACTION: Self; NbExp=16; IntAct=EBI-681210, EBI-681210; P35609:ACTN2; NbExp=7; IntAct=EBI-681210, EBI-77797; P20807:CAPN3; NbExp=3; IntAct=EBI-681210, EBI-5655000; O75953:DNAJB5; NbExp=4; IntAct=EBI-681210, EBI-5655937; O75923:DYSF; NbExp=17; IntAct=EBI-681210, EBI-2799016; P06733:ENO1; NbExp=3; IntAct=EBI-681210, EBI-353877; Q14324:MYBPC2; NbExp=14; IntAct=EBI-681210, EBI-5653200; Q13203:MYBPH; NbExp=3; IntAct=EBI-681210, EBI-5655165; P54296:MYOM2; NbExp=2; IntAct=EBI-681210, EBI-5357134; Q5VST9:OBSCN; NbExp=4; IntAct=EBI-681210, EBI-941850; Q96CV9:OPTN; NbExp=2; IntAct=EBI-681210, EBI-748974; O15273:TCAP; NbExp=4; IntAct=EBI-681210, EBI-954089; SUBCELLULAR LOCATION: Cytoplasm (Probable). Nucleus. 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 familial hypertrophic cardiomyopathy type 9 (CMH9) [MIM:613765]. 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; Sequence=CAA62188.1; Type=Frameshift; Positions=17036, 17043; Sequence=CAD12455.1; Type=Frameshift; Positions=17036, 17043; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TTN"; WEB RESOURCE: Name=Wikipedia; Note=Titin entry; URL="http://en.wikipedia.org/wiki/Titin";
Heart Rate Fabio Marroni et al. Circulation. Cardiovascular genetics 2009, A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project., Circulation. Cardiovascular genetics.
[PubMed 20031603]
Our results suggested an association between the RR interval and GPR133 and confirmed an association between the QT interval and NOS1AP.
Hip Douglas P Kiel et al. BMC medical genetics 2007, Genome-wide association with bone mass and geometry in the Framingham Heart Study., BMC medical genetics.
[PubMed 17903296]
The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.
Lipids Sekar Kathiresan et al. BMC medical genetics 2007, A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study., BMC medical genetics.
[PubMed 17903299]
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q8WZ42
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
US Server
