Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity

TLDR

Vertebrate striated muscle contains a third filament system, titin, which extends from Z discs to M lines, exceeds 1 µm in length, and contributes to muscle assembly and resting tension, though its detailed role remains unclear due to its size. The complete cDNA sequence of human cardiac titin was determined. The 82‑kb cDNA predicts a 3‑MDa titin protein with 244 Ig and FN3 domains, whose A‑band architecture explains conserved thick‑filament structure and whose I‑band elements correlate with tissue stiffness, indicating titin functions as two springs in series whose differential expression accounts for vertebrate sarcomere length and resting tension diversity.

Abstract

In addition to thick and thin filaments, vertebrate striated muscle contains a third filament system formed by the giant protein titin. Single titin molecules extend from Z discs to M lines and are longer than 1 micrometer. The titin filament contributes to muscle assembly and resting tension, but more details are not known because of the large size of the protein. The complete complementary DNA sequence of human cardiac titin was determined. The 82-kilobase complementary DNA predicts a 3-megadalton protein composed of 244 copies of immunoglobulin and fibronectin type III (FN3) domains. The architecture of sequences in the A band region of titin suggests why thick filament structure is conserved among vertebrates. In the I band region, comparison of titin sequences from muscles of different passive tension identifies two elements that correlate with tissue stiffness. This suggests that titin may act as two springs in series. The differential expression of the springs provides a molecular explanation for the diversity of sarcomere length and resting tension in vertebrate striated muscles.