The Giant Protein Titin

Abstract

Titin is a giant protein of vertebrate striated muscles ( M r , ≥3000 kD). Its molecules are of filamentous shape and span from the Z disk to the M line, thereby forming a third filament system of the sarcomere. This filament system is important for both the structural integrity of the myofibril and the passive tension response of a stretched muscle fiber. The determination of the cDNA sequence of human cardiac titin has shown that the cardiac titin filament is formed by a single, giant, 27 000-residue-long polypeptide chain. The titin strand has a modular structure, and different modulular arrangements are expressed in different muscle tissue types by differential splicing. In the A band, the titin modules provide regular arrays of binding sites for other sarcomeric proteins, thereby contributing to a precise assembly of myofibrillar proteins in vivo. In the I band, two specific motif families, tandem-immunoglobulin domains and PEVK-rich sequences, confer extensibility to the titin filament. Expression of muscle tissue–specific length variants of the PEVK region by alternative splicing may explain the differences in the passive tension properties between various striated muscle types. Apart from the titin sequences with apparent functions for muscle structure and elasticity, the titin molecule contains a class of unique sequence insertions. Among these sequences are phosphorylation sites, a serine/threonine kinase domain, and binding sites for muscle-specific calpain proteases. Thus, it is likely that the titin filament also plays a role in myofibrillar signal transduction pathways.