Effects of myosin variants on interacting heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes
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Author(s)
Type
Journal Article
Abstract
Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.
Date Issued
2017-06-13
Online Publication Date
2017-06-13
2017-09-19T11:16:04Z
Date Acceptance
2017-05-05
ISSN
2050-084X
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
Journal / Book Title
ELIFE
Volume
6
Copyright Statement
© 2017 Alamo et al. This
article is distributed under the
terms of the Creative Commons
Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
article is distributed under the
terms of the Creative Commons
Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
Source Database
pubmed
Sponsor
Wellcome Trust
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000403160500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
107469/Z/15/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
BINDING-PROTEIN-C
BETA-CARDIAC MYOSIN
SUPER-RELAXED STATE
SKELETAL-MUSCLE
GENETIC-VARIATION
HEAVY-MEROMYOSIN
FORCE GENERATION
CHAIN MUTATIONS
MOLECULAR MOTOR
THICK FILAMENT
cardiomyopathy
diastolic heart disease
human
human biology
human mutation
medicine
myosin interacting-heads motif
super-relaxation
β-cardiac myosin
Publication Status
Published
Article Number
ARTN e24634