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      Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism

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          Abstract

          Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A from Plasmodium falciparum (PfMyoA) is critical for red blood cell invasion. Further, using a combination of X-ray crystallography, kinetics, and in vitro motility assays, we elucidate the non-canonical interactions that drive this motor’s function. We show that PfMyoA motor properties are tuned by heavy chain phosphorylation (Ser19), with unphosphorylated PfMyoA exhibiting enhanced ensemble force generation at the expense of speed. Regulated phosphorylation may therefore optimize PfMyoA for enhanced force generation during parasite invasion or for fast motility during dissemination. The three PfMyoA crystallographic structures presented here provide a blueprint for discovery of specific inhibitors designed to prevent parasite infection.

          Abstract

          Here, Robert-Paganin et al. show that myosin A from Plasmodium falciparum is critical for red blood cell invasion and that non-canonical interactions and regulated phosphorylation are important for force generation during parasite invasion.

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          Most cited references 27

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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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            Conditional genome engineering in Toxoplasma gondii uncovers alternative invasion mechanisms

            We established a conditional site–specific recombination system based on dimerizable Cre–mediated recombination in the apicomplexan parasite Toxoplasma gondii. Using a novel single vector strategy that allows ligand-dependent, efficient removal of a gene of interest, we generated three knockouts of apicomplexan genes considered essential for host-cell invasion. Our findings uncover the existence of an alternative invasion pathway in apicomplexan parasites.
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              Purification of muscle actin.

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                Author and article information

                Contributors
                kathleen.trybus@uvm.edu
                anne.houdusse@curie.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                23 July 2019
                23 July 2019
                2019
                : 10
                Affiliations
                [1 ]Structural Motility, UMR 144 CNRS/Curie Institute, 26 rue d’ulm, 75258 Paris cedex 05, France
                [2 ]ISNI 0000 0004 1936 7689, GRID grid.59062.38, Department of Molecular Physiology and Biophysics, , University of Vermont, ; Burlington, VT 05405 USA
                [3 ]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
                [4 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Life Sciences, , Imperial College London, ; Exhibition Road, South Kensington, London SW7 2AZ UK
                Article
                11120
                10.1038/s41467-019-11120-0
                6650474
                © The Author(s) 2019

                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: National Institutes of Health grant AI 132378 programme grant from the Human Frontier Science Program (RGY0066/2016)
                Funded by: PhD studentship from the Wellcome ((109007/Z/15/A)
                Funded by: PhD studentship from Sorbonne Paris Cité (École Doctorale Complexité du Vivant).
                Funded by: National Institutes of Health grant HL 124041
                Funded by: programme grant from the Human Frontier Science Program (RGY0066/2016) Investigator Award (100993/Z/13/Z
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized

                hydrolases, motor protein function, x-ray crystallography, malaria

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