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      Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

      1 , , 2 , , 1

      Nature Communications

      Nature Publishing Group UK

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          Abstract

          Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. Here, we present an optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm, allowing the systematic study of a large set of HCM mutations and the definition of different mutation classes based on their effects on lever arm compliance, sequestered state stability, and motor functions. The present work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.

          Abstract

          Hypertrophic cardiomyopathy (HCM) is caused by point mutations in sarcomeric proteins. Here the authors develop an optimized model of the sequestered state of cardiac myosin and define the features affecting the lever arm compliance, allowing them to group mutations in classes and to elucidate the molecular mechanisms leading to cardiac dysfunction in HCM.

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          Most cited references 40

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          Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

          Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.
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            Atomic model of a myosin filament in the relaxed state.

            Contraction of muscle involves the cyclic interaction of myosin heads on the thick filaments with actin subunits in the thin filaments. Muscles relax when this interaction is blocked by molecular switches on either or both filaments. Insight into the relaxed (switched OFF) structure of myosin has come from electron microscopic studies of smooth muscle myosin molecules, which are regulated by phosphorylation. These studies suggest that the OFF state is achieved by an asymmetric, intramolecular interaction between the actin-binding region of one head and the converter region of the other, switching both heads off. Although this is a plausible model for relaxation based on isolated myosin molecules, it does not reveal whether this structure is present in native myosin filaments. Here we analyse the structure of a phosphorylation-regulated striated muscle thick filament using cryo-electron microscopy. Three-dimensional reconstruction and atomic fitting studies suggest that the 'interacting-head' structure is also present in the filament, and that it may underlie the relaxed state of thick filaments in both smooth and myosin-regulated striated muscles over a wide range of species.
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              Three-dimensional image reconstruction of dephosphorylated smooth muscle heavy meromyosin reveals asymmetry in the interaction between myosin heads and placement of subfragment 2.

              Regulation of the actin-activated ATPase of smooth muscle myosin II is known to involve an interaction between the two heads that is controlled by phosphorylation of the regulatory light chain. However, the three-dimensional structure of this inactivated form has been unknown. We have used a lipid monolayer to obtain two-dimensional crystalline arrays of the unphosphorylated inactive form of smooth muscle heavy meromyosin suitable for structural studies by electron cryomicroscopy of unstained, frozen-hydrated specimens. The three-dimensional structure reveals an asymmetric interaction between the two myosin heads. The ATPase activity of one head is sterically "blocked" because part of its actin-binding interface is positioned onto the converter domain of the second head. ATPase activity of the second head, which can bind actin, appears to be inhibited through stabilization of converter domain movements needed to release phosphate and achieve strong actin binding. When the subfragment 2 domain of heavy meromyosin is oriented as it would be in an actomyosin filament lattice, the position of the heads is very different from that needed to bind actin, suggesting an additional contribution to ATPase inhibition in situ.
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                Author and article information

                Contributors
                auguin@univ-orleans.fr
                anne.houdusse@curie.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                1 October 2018
                1 October 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000 0001 2112 9282, GRID grid.4444.0, Structural Motility, Institut Curie, , PSL Research University, CNRS, UMR 144, ; F-75005 Paris, France
                [2 ]ISNI 0000 0001 0217 6921, GRID grid.112485.b, Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), , Université d’Orléans, INRA, USC1328, ; 45067 Orléans, France
                Article
                6191
                10.1038/s41467-018-06191-4
                6167380
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100007393, Association Française contre les Myopathies (AFM);
                Award ID: 17235
                Award ID: 18423
                Award Recipient :
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