Pernigo, Stefano, Fukuzawa, Atsushi, Beedle, Amy E.M., Holt, Mark, Round, Adam, Pandini, Alessandro, Garcia-Manyes, Sergi, Gautel, Mathias and Steiner, Roberto A. (2017) Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection. Structure, 25 (1). pp. 107-120.

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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.

Item Type: Article
Uncontrolled Keywords: muscle, M-band, myomesin, obscurin, obscurin-like-1, protein complexes, X-ray crystallography, SAXS, atomic force microscopy, immunoglobulin domain
Subjects: Q Science > QD Chemistry
Q Science > QD Chemistry > QD415 Biochemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Depositing User: Mr Scott McGowan
Date Deposited: 25 Jan 2017 11:37
Last Modified: 02 Apr 2019 15:40
URI: http://eprints.keele.ac.uk/id/eprint/2821

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