Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex

Stefano Pernigo, Atsushi Fukuzawa, Morten Bertz, Mark Holt, Matthias Rief, Roberto A. Steiner, Mathias Gautel

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

In the sarcomeric M-band, the giant ruler proteins titin and obscurin, its small homologue obscurin-like-1 (obsl1), and the myosin cross-linking protein myomesin form a ternary complex that is crucial for the function of the M-band as a mechanical link. Mutations in the last titin immunoglobulin (Ig) domain M10, which interacts with the N-terminal Ig-domains of obscurin and obsl1, lead to hereditary muscle diseases. The M10 domain is unusual not only in that it is a frequent target of disease-linked mutations, but also in that it is the only currently known muscle Ig-domain that interacts with two ligands - obscurin and obsl1 - in different sarcomeric subregions. Using x-ray crystallography, we show the structural basis for titin M10 interaction with obsl1 in a novel antiparallel Ig-Ig architecture and unravel the molecular basis of titin-M10 linked myopathies. The severity of these pathologies correlates with the disruption of the titin-obsl1/obscurin complex. Conserved signature residues at the interface account for differences in affinity that direct the cellular sorting in cardiomyocytes. By engineering the interface signature residues of obsl1 to obscurin, and vice versa, their affinity for titin can be modulated similar to the native proteins. In single-molecule force-spectroscopy experiments, both complexes yield at forces of around 30 pN, much lower than those observed for the mechanically stable Z-disk complex of titin and telethonin, suggesting why even moderate weakening of the obsl1/obscurintitin links has severe consequences for normal muscle functions.

Original languageEnglish
Pages (from-to)2908-2913
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
Publication statusPublished - 2010 Feb 16
Externally publishedYes

Keywords

  • Immunoglobulin domain
  • Mechanosensor
  • Myopathy
  • Protein complex
  • X-ray crystallography

ASJC Scopus subject areas

  • General

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