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

Stefano Pernigo; Atsushi Fukuzawa; Amy E M Beedle; Mark Holt; Adam Round; Alessandro Pandini; Sergi Garcia-Manyes; Mathias Gautel; Roberto A. Steiner

doi:10.1016/j.str.2016.11.015

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

Stefano Pernigo, Atsushi Fukuzawa, Amy E M Beedle, Mark Holt, Adam Round, Alessandro Pandini, Sergi Garcia-Manyes^*, Mathias Gautel, Roberto A. Steiner

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	107-120
Number of pages	14
Journal	Structure
Volume	25
Issue number	1
Early online date	15 Dec 2016
DOIs	https://doi.org/10.1016/j.str.2016.11.015
Publication status	Published - 3 Jan 2017

Keywords

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

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10.1016/j.str.2016.11.015Licence: CC BY

Binding of Myomesin_PERNIGO_Firstonline15December2016_GOLD VoR (CC-BY)Final published version, 4.83 MBLicence: CC BY

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

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.",

keywords = "atomic force microscopy, immunoglobulin domain, M-band, muscle, myomesin, obscurin, obscurin-like-1, protein complexes, SAXS, X-ray crystallography",

author = "Stefano Pernigo and Atsushi Fukuzawa and Beedle, {Amy E M} and Mark Holt and Adam Round and Alessandro Pandini and Sergi Garcia-Manyes and Mathias Gautel and Steiner, {Roberto A.}",

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AU - Pernigo, Stefano

AU - Fukuzawa, Atsushi

AU - Beedle, Amy E M

AU - Holt, Mark

AU - Round, Adam

AU - Pandini, Alessandro

AU - Garcia-Manyes, Sergi

AU - Gautel, Mathias

AU - Steiner, Roberto A.

PY - 2017/1/3

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N2 - 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.

AB - 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.

KW - atomic force microscopy

KW - immunoglobulin domain

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KW - X-ray crystallography

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

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Keywords

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