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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
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
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
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I04-Macromolecular Crystallography
Other Facilities: European Synchrotron Radiation Laboratory
Added On:
19/01/2017 10:46
Documents:
1-s2.0-S0969212616303574-main.pdf
Discipline Tags:
Structural biology
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)