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titin (connectin, rhabdomyosarcoma antigen MU-RMS-40.14, TTN)
Titin molecules extend from sarcomeric Z-bands to M-lines, & are crucial for myofibrillar elasticity & integrity. Mutations associated with familial dilated cardiomyopathy
Function:
1) assembly & functioning of vertebrate striated muscles
2) connections between individual microfilaments
3) balance of forces between 2 halves of sarcomere
4) in non-muscle cells, plays a role in chromosome condensation & chromosome segregation during mitosis
5) links lamina network to chromatin or nuclear actin, or both during interphase (putative)
6) activation of the protein kinase domain requires both Tyr phosphorylation & calmodulin-binding
7) interacts with MYOM1, MYOM2, tropomyosin,myosin, actin (via PEVK domains), MYPN, FHL2, NEB, CRYAB, LMNA/lamin-A, LMNB/lamin-B, TCAP/telethonin, ANK1 isoform Mu17/ank1.5 (via 1st 2 N-terminal immunoglobulin domains) TRIM63, TRIM55, ANKRD1, ANKRD2, ANKRD23,CAPN3, NBR1 (via protein kinase domain), CALM/calmodulin
8) ZIS1 & ZIS5 regions contain multiple SPXR consensus sites for ERK- & CDK-like protein kinases & multiple SP motifs
9) ZIS1 could adopt a closed conformation which would block TCAP-binding site.
10) PEVK region may serve as an 'entropic spring of a chain of structural folds' & may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere
11) autophosphorylated
ATP + a protein ADP + a phosphoprotein
Structure:
1) contains 132 fibronectin F3 modules
- contains 152 Ig-like domains (immunoglobulin-like)
- contains 19 Kelch repeats
- contains 1 protein kinase domain
- contains 17 RCC1 repeats
- contains 14 TPR repeats
- contains 15 WD repeats
2) In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region
- on account of this region, it has been difficult to sequence the whole protein
- length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin
Alternative splicing: named isoforms=8 Isoform 3,7,8 are expressed in cardiac muscle Isoform 4 is expressed in vertebrate skeletal muscle Isoform 6 is expressed in cardiac tissues.
Pathology:
1) defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF)
2) defects in TTN are the cause of familial hypertrophic cardiomyopathy type 9
3) defects in TTN are the cause of dilated cardiomyopathy 1G
4) defects in TTN are the cause of tardive-tibial muscular dystrophy
5) defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J)
Laboratory:
- titin Ab in serum
- titin IgG in serum
General
microfilament protein
tyrosine kinase (protein tyrosine kinase, PTK)
Properties
COMPARTMENT: cytoplasm
STATE: active state
MOTIF: coiled coil
Database Correlations
OMIM correlations
UniProt Q8WZ42
PFAM correlations
Entrez Gene 7273
ENZYME 2.7.11.1
References
- Gerull et al. Nature genetics 30:201-4, 2002
- UniProt :accession Q8WZ42
- GeneReviews
https://www.genecards.org/cgi-bin/carddisp.pl?gene=TTN
- Wikipedia; Note: Titin entry
http://en.wikipedia.org/wiki/Titin