| Structural highlights
Disease
TITIN_HUMAN 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.[1] 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.[2] 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.[3] [4] [5] 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.[6] [7] 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. 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.[8]
Function
TITIN_HUMAN 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.[9]
Publication Abstract from PubMed
Striated muscle tissues undergo adaptive remodelling in response to mechanical load. This process involves the myofilament titin and, specifically, its kinase domain (TK; titin kinase) that translates mechanical signals into regulatory pathways of gene expression in the myofibril. TK mechanosensing appears mediated by a C-terminal regulatory tail (CRD) that sterically inhibits its active site. Allegedly, stretch-induced unfolding of this tail during muscle function releases TK inhibition and leads to its catalytic activation. However, the cellular pathway of TK is poorly understood and substrates proposed to date remain controversial. TK's best-established substrate is Tcap, a small structural protein of the Z-disc believed to link TK to myofibrillogenesis. Here, we show that TK is a pseudokinase with undetectable levels of catalysis and, therefore, that Tcap is not its substrate. Inactivity is the result of two atypical residues in TK's active site, M34 and E147, that do not appear compatible with canonical kinase patterns. While not mediating stretch-dependent phospho-transfers, TK binds the E3 ubiquitin ligase MuRF1 that promotes sarcomeric ubiquitination in a stress-induced manner. Given previous evidence of MuRF2 interaction, we propose that the cellular role of TK is to act as a conformationally regulated scaffold that functionally couples the ubiquitin ligases MuRF1 and MuRF2, thereby coordinating muscle-specific ubiquitination pathways and myofibril trophicity. Finally, we suggest that an evolutionary dichotomy of kinases/pseudokinases has occurred in TK-like kinases, where invertebrate members are active enzymes but vertebrate counterparts perform their signalling function as pseudokinase scaffolds.
Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.,Bogomolovas J, Gasch A, Simkovic F, Rigden DJ, Labeit S, Mayans O Open Biol. 2014 May;4(5):140041. doi: 10.1098/rsob.140041. PMID:24850911[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. Epub 2005 Mar 31. PMID:15802564 doi:1110463
- ↑ 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. 1999 Aug 27;262(2):411-7. PMID:10462489 doi:10.1006/bbrc.1999.1221
- ↑ 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. 2002 Feb 22;291(2):385-93. PMID:11846417 doi:10.1006/bbrc.2002.6448
- ↑ Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, 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. 2002 Feb;30(2):201-4. Epub 2002 Jan 14. PMID:11788824 doi:10.1038/ng815
- ↑ 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. 2005;26(6-8):367-74. PMID:16465475 doi:10.1007/s10974-005-9018-5
- ↑ 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. 2002 Sep;71(3):492-500. Epub 2002 Jul 26. PMID:12145747 doi:S0002-9297(07)60330-9
- ↑ Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B. Tibial muscular dystrophy in a Belgian family. Ann Neurol. 2003 Aug;54(2):248-51. PMID:12891679 doi:10.1002/ana.10647
- ↑ Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007 Apr;61(4):340-51. PMID:17444505 doi:10.1002/ana.21089
- ↑ Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Furst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature. 1998 Oct 29;395(6705):863-9. PMID:9804419 doi:10.1038/27603
- ↑ Bogomolovas J, Gasch A, Simkovic F, Rigden DJ, Labeit S, Mayans O. Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line. Open Biol. 2014 May;4(5):140041. doi: 10.1098/rsob.140041. PMID:24850911 doi:http://dx.doi.org/10.1098/rsob.140041
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