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      The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin

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          Abstract

          Hypertrophic cardiomyopathy–causing mutations disrupt a key regulatory off state of myosin in thick filaments.

          Abstract

          Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin and myosin binding protein-C (MyBP-C) lead to hypercontractility of the heart, an early hallmark of HCM. We show that hypercontractility caused by the HCM-causing mutation R663H cannot be explained by changes in fundamental myosin contractile parameters, much like the HCM-causing mutation R403Q. Using enzymatic assays with purified human β-cardiac myosin, we provide evidence that both mutations cause hypercontractility by increasing the number of functionally accessible myosin heads. We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of MyBP-C. Furthermore, addition of C0-C7 decreases the wild-type myosin basal ATPase single turnover rate, while the mutants do not show a similar reduction. These data suggest that a primary mechanism of action for these mutations is to increase the number of myosin heads functionally available for interaction with actin, which could contribute to hypercontractility.

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          Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.

          Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.
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            Cellular mechanisms of cardiomyopathy

            The heart exhibits remarkable adaptive responses to a wide array of genetic and extrinsic factors to maintain contractile function. When compensatory responses are not sustainable, cardiac dysfunction occurs, leading to cardiomyopathy. The many forms of cardiomyopathy exhibit a set of overlapping phenotypes reflecting the limited range of compensatory responses that the heart can use. These include cardiac hypertrophy, induction of genes normally expressed during development, fibrotic deposits that replace necrotic and apoptotic cardiomyocytes, and metabolic disturbances. The compensatory responses are mediated by signaling pathways that initially serve to maintain normal contractility; however, persistent activation of these pathways leads to cardiac dysfunction. Current research focuses on ways to target these specific pathways therapeutically.
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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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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                April 2020
                03 April 2020
                : 6
                : 14
                : eaax0069
                Affiliations
                [1 ]Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
                [2 ]Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
                [3 ]National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.
                [4 ]Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: jspudich@ 123456stanford.edu (J.A.S.); kruppel@ 123456stanford.edu (K.M.R.)
                Author information
                http://orcid.org/0000-0003-0535-9330
                http://orcid.org/0000-0002-4188-3570
                http://orcid.org/0000-0001-7561-892X
                http://orcid.org/0000-0002-0971-5331
                http://orcid.org/0000-0002-4324-4254
                Article
                aax0069
                10.1126/sciadv.aax0069
                7124958
                32284968
                c78febc3-f389-4eb1-b658-8038ce5fa82e
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 16 February 2019
                : 09 January 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000052, NIH Office of the Director;
                Award ID: GM33289
                Funded by: doi http://dx.doi.org/10.13039/100000052, NIH Office of the Director;
                Award ID: HL117138
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Health and Medicine
                Biochemistry
                Custom metadata
                Adrienne Del Mundo

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