Probing the Functional Roles of Titin Ligands in Cardiac Myofibril Assembly and Maintenance
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Sarcomeres of cardiac muscle are comprised of numerous proteins organized in an elegantly precise order. The exact mechanism of how these proteins are assembled into myofibrils during heart development is not yet understood, although existing in vitro and in vivo model systems have provided great insight into this complex process. It has been proposed by several groups that the giant elastic protein titin acts as a “molecular template” to orchestrate sarcomeric organization during myofibrillogenesis. Titin’s highly modular structure, composed of both repeating and unique domains that interact with a wide spectrum of contractile and regulatory ligands, supports this hypothesis. Recent functional studies have provided clues to the physiological significance of the interaction of titin with several titin-binding proteins in the context of live cardiac cells. Improved models of cardiac myofibril assembly, along with the application of powerful functional studies in live cells, as well as the characterization of additional titin ligands, is likely to reveal surprising new functions for the titin third filament system.
KeywordsCardiac Myocytes Thin Filament Thick Filament Somite Stage Familial Hypertrophic Cardiomyopathy
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- Fürst DO, Osborn M, Nave R, Weber K. The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: A map of ten nonrepetitive epitopes starting at the Z-line extends close to the M-line. J Cell Biol 1988;106:1563–1572.PubMedCrossRefGoogle Scholar
- Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S. The NH2 terminus of titin spans the Z-disc; Its interaction with a novel 19 kD ligand (T-cap) is required for sarcomeric integrity. J Cell Biol 1998;143:1013–1027.PubMedCrossRefGoogle Scholar
- Hill CS, Lemanski LF. Immunoelectron microscopic localization of alpha actinin and actin in embryonic hamster heart cells. Euro J Cell Biol 1985;39:300–312.Google Scholar
- Hiruma T, Hirakow R. An ultrastructural topographical study on myofibrillogenesis in the heart of the chick embryo during pulsation onset period. Dev Dyn 1985;196:291–299.Google Scholar
- Obermann WMJ, Gautel M, Steiner F, van der Ven PFM, Weber K, Fürst DO. The structure of the sarcomeric M band: localization of defined domains of myomesin, M protein, and the 250 kD carboxy terminal region of titin by immunoelectron microscopy. J Cell Biol 1996;134:1441–1453.PubMedCrossRefGoogle Scholar
- Rudy DE, Yatskievych TA, Antin PB, Gregorio CC. Investigation of the assembly of thick, thin and titin filaments in chick precardiac explants. Mol Biol Cell 1999;10:980.Google Scholar
- Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K, Suzuki K. Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J Biol Chem 1995;270:31158–31162.PubMedCrossRefGoogle Scholar
- Tardiff JC, Factor SM, Tompkins BD, Hewett TE, Palmer BM, Moore RL, Schwartz S, Robbins J, Leinwand LA. A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest 1998;101:2800–2811.PubMedCrossRefGoogle Scholar
- Wang K, Knipfer M, Huang Q, van Heerden A, Hsu LC, Gutierrez G, Quian X, Stedman H. Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem 1996;271:4304–4314.PubMedCrossRefGoogle Scholar
- Wobus AM, Kaomei G, Shan J, Wellner MC, Rohwedel J, Guanju J, Fleischmann B, Katus HA, Hescheler J, Franz WM. Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes. J Mol Cell Cardiol 1997;29:1525–1539.PubMedCrossRefGoogle Scholar