Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection

Structure. 2017 Jan 3;25(1):107-120. doi: 10.1016/j.str.2016.11.015. Epub 2016 Dec 15.


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.

Keywords: M-band; SAXS; X-ray crystallography; atomic force microscopy; immunoglobulin domain; muscle; myomesin; obscurin; obscurin-like-1; protein complexes.

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Connectin / chemistry*
  • Connectin / metabolism*
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry*
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeleton / metabolism
  • Humans
  • Immunoglobulins / metabolism
  • Models, Molecular
  • Muscle, Skeletal / metabolism
  • Myocytes, Cardiac / metabolism
  • Protein Binding
  • Protein Domains
  • Protein Serine-Threonine Kinases
  • Rats
  • Rho Guanine Nucleotide Exchange Factors / chemistry*
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Sarcomeres / metabolism


  • Connectin
  • Cytoskeletal Proteins
  • Immunoglobulins
  • MYOM1 protein, human
  • OBSL1 protein, human
  • Rho Guanine Nucleotide Exchange Factors
  • OBSCN protein, human
  • Protein Serine-Threonine Kinases