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      Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

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          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.

          DOI: http://dx.doi.org/10.7554/eLife.24634.001

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          Most cited references 66

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          Three-dimensional structure of myosin subfragment-1: a molecular motor.

          Directed movement is a characteristic of many living organisms and occurs as a result of the transformation of chemical energy into mechanical energy. Myosin is one of three families of molecular motors that are responsible for cellular motility. The three-dimensional structure of the head portion of myosin, or subfragment-1, which contains both the actin and nucleotide binding sites, is described. This structure of a molecular motor was determined by single crystal x-ray diffraction. The data provide a structural framework for understanding the molecular basis of motility.
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            Accurate SAXS profile computation and its assessment by contrast variation experiments.

            A major challenge in structural biology is to characterize structures of proteins and their assemblies in solution. At low resolution, such a characterization may be achieved by small angle x-ray scattering (SAXS). Because SAXS analyses often require comparing profiles calculated from many atomic models against those determined by experiment, rapid and accurate profile computation from molecular structures is needed. We developed fast open-source x-ray scattering (FoXS) for profile computation. To match the experimental profile within the experimental noise, FoXS explicitly computes all interatomic distances and implicitly models the first hydration layer of the molecule. For assessing the accuracy of the modeled hydration layer, we performed contrast variation experiments for glucose isomerase and lysozyme, and found that FoXS can accurately represent density changes of this layer. The hydration layer model was also compared with a SAXS profile calculated for the explicit water molecules in the high-resolution structures of glucose isomerase and lysozyme. We tested FoXS on eleven protein, one DNA, and two RNA structures, revealing superior accuracy and speed versus CRYSOL, AquaSAXS, the Zernike polynomials-based method, and Fast-SAXS-pro. In addition, we demonstrated a significant correlation of the SAXS score with the accuracy of a structural model. Moreover, FoXS utility for analyzing heterogeneous samples was demonstrated for intrinsically flexible XLF-XRCC4 filaments and Ligase III-DNA complex. FoXS is extensively used as a standalone web server as a component of integrative structure determination by programs IMP, Chimera, and BILBOMD, as well as in other applications that require rapidly and accurately calculated SAXS profiles. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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              The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.

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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                13 June 2017
                2017
                : 6
                Affiliations
                [1 ]deptCentro de Biología Estructural , Instituto Venezolano de Investigaciones Científicas , Caracas, Venezuela
                [2 ]deptNational Heart and Lung Institute and MRC London Institute for Medical Sciences , Imperial College London , London, United Kingdom
                [3 ]deptNIHR Cardiovascular Biomedical Research Unit , Royal Brompton and Harefield NHS Foundation Trust and Imperial College London , London, United Kingdom
                [4 ]deptDepartment of Genetics , Harvard Medical School , Boston, United States
                [5 ]deptMacromolecular Diffraction Facility , Cornell High Energy Synchrotron Source , Ithaca, United States
                [6 ]deptCardiovascular Division , Brigham and Women’s Hospital and Howard Hughes Medical Institute , Boston, United States
                Cincinnati Children's Hospital Medical Center, University of Cincinnati , United States
                Cincinnati Children's Hospital Medical Center, University of Cincinnati , United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Article
                24634
                10.7554/eLife.24634
                5469618
                28606303
                © 2017, Alamo et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NHLBI-HL084553
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 107469/Z/15/Z
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM-103485
                Award Recipient :
                Funded by: Foundation Leducq;
                Award ID: 11CVD-01
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Human Biology and Medicine
                Custom metadata
                2.5
                Mapping the locations of hypertrophic cardiomyopathy gene variants onto the three-dimensional structures of contractile proteins revealed that these disrupt protein interactions are critical for normal cardiac relaxation and efficient energy usage.

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