Titin Gene ( TTN ): Description of the Gene Coding for Titin, a Giant Protein of Critical Importance for Myofibrillar Integrity and Elasticity in Vertebrate Striated Muscle

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Abstract Up to 34 350 residues long, titin is the largest protein described to date. The titin locus in human located on chromosome 2q24 expresses up to 100 kb (kilobase) full‐length mRNAs (messenger ribonucleic acid) that are translated into giant polypeptides. Titin is an abundant vertebrate muscle protein, spanning half of the sarcomere. In situ , 1–2 μ m long titin polypeptides establish a sarcomeric filament system that is critical for myofibrillar integrity and elasticity. Biomechanically, the titin filament is a fine‐tuned component of the muscle passive force that is regulated trough alternative splicing, posttranslational modifications and protein–protein interactions. A variety of molecular interactions with stress‐regulated ligands position titin centrally in stretch‐dependent signalling in muscle. Consistent with this, a plethora of mutations in the titin filament system cause hereditary myopathies affecting heart, diaphragm and skeletal muscles. In particular, stop codons in one titin allele are a major cause of hereditary dilative cardiomyopathy. Key Concepts Sarcomeres consist of precisely assembled proteins that together form the basic functional units of striated muscle and that give rise to efficient and finely tuned contraction. In muscle tissues, 1 – 2 µm single titin polypeptide chains span half of the sarcomere. The intrasarcomeric filamentous titin protein provides sarcomeres with intrinsic elasticity and couples stretch‐dependent signalling to muscle remodelling. Titin molecule is tailored to physiological requirements of different muscles through alternative splicing, posttranslational modifications and protein – protein interactions. Consistent with titin's central role in muscle biology, mutations in its gene cause myopathies in heart, skeletal and diaphragm muscle tissues.

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