26 Citations (Scopus)
215 Downloads (Pure)

Abstract

The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signaling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1):myomesin complex. The crystal structure reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. Crucially, this unconventional architecture provides mechanical stability up to forces of ∼135 pN. A cellular competition assay in neonatal rat cardiomyocytes validates the complex and provides the rationale for the isoform specificity of the interaction. Altogether, our results reveal a novel binding strategy in sarcomere assembly, which might have implications on muscle nanomechanics and overall M-band organization.

Original languageEnglish
Pages (from-to)107-120
Number of pages14
JournalStructure
Volume25
Issue number1
Early online date15 Dec 2016
DOIs
Publication statusPublished - 3 Jan 2017

Keywords

  • atomic force microscopy
  • immunoglobulin domain
  • M-band
  • muscle
  • myomesin
  • obscurin
  • obscurin-like-1
  • protein complexes
  • SAXS
  • X-ray crystallography

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