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Titinless mice

Without titin's kinase domain, the heart initially develops properly (left), but degenerates under strain (right).

Titin needs no kinase activity to assemble sarcomeres, the building blocks of muscle tissue, according to Weinert et al. (page 559).

The giant protein called titin is a major component of muscles. Its COOH terminus, also known as the M-line region, includes a kinase-like domain. In yeast two-hybrid assays, titin's M-line interacts with proteins that shuttle to and from the nucleus, leading scientists to believe that it might initiate sarcomere assembly via signaling pathways.

A mouse strain lacking the kinase-like domain and nearby regions, however, reveals that the domain is not necessary for sarcomere assembly. These mice died during embryogenesis, but histological images revealed that sarcomere assembly and heart formation were initially normal. The lethal defect was heart failure due to a lack of sarcomere thickening—the addition of more actin and myosin filaments.

Recently identified signaling proteins that control muscle gene expression, and protein turnover via the kinase domain were not expressed during embryogenesis in wild-type or mutant mice. The effects thus seem to be mostly structural, unless as-yet unidentified kinase targets are required. In the deletion strain muscles, titin tails failed to overlap with neighboring molecules and were swinging freely, locked down on only one end.

Myomesin, a protein that links actin filaments, also binds to a titin region lost in the deletion. Weinert believes its lost binding site may lead to loosely packed filaments that impair the stabililty of the sarcomere.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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Related Article

M line–deficient titin causes cardiac lethality through impaired maturation of the sarcomere

Stefanie Weinert, Nora Bergmann, Xiuju Luo, Bettina Erdmann, and Michael Gotthardt
J. Cell Biol. 2006 173: 559-570. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 761K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                            What's this?