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

DOI: 10.1016/j.str.2016.11.015 DOI Help

Authors: Stefano Pernigo (King's College London) , Atsushi Fukuzawa (King's College London) , Amy E. M. Beedle (King's College London) , Mark Holt (King's College London) , Adam Round (European Molecular Biology Laboratory, Grenoble Outstation; Keele University) , Alessandro Pandini (King's College London; Brunel University London) , Sergi Garcia-manyes (King's College London) , Mathias Gautel (King's College London) , Roberto A. Steiner (King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 25 , PAGES 107 - 120

State: Published (Approved)
Published: January 2017

Open Access Open Access

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.

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

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Laboratory


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