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|Title:||Binding of myomesin to obscurin-like-1 to the muscle M-band provides a strategy for isoform-specific mechanical protection|
|Keywords:||Muscle;M-band;Myomesin;Obscurin;Obscurin-like-1;Protein complexes;X-ray crystallography;SAXS;Atomic force microscopy;Immunoglobulin domain|
|Citation:||Structure, 25: pp. 1-14, (2017)|
|Abstract:||The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signalling 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.|
|Appears in Collections:||Dept of Computer Science Research Papers|
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