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      The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects*

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          The embryonic myosin isoform is expressed during fetal development and rapidly down-regulated after birth. Freeman-Sheldon syndrome (FSS) is a disease associated with missense mutations in the motor domain of this myosin. It is the most severe form of distal arthrogryposis, leading to overcontraction of the hands, feet, and orofacial muscles and other joints of the body. Availability of human embryonic muscle tissue has been a limiting factor in investigating the properties of this isoform and its mutations. Using a recombinant expression system, we have studied homogeneous samples of human motors for the WT and three of the most common FSS mutants: R672H, R672C, and T178I. Our data suggest that the WT embryonic myosin motor is similar in contractile speed to the slow type I/β cardiac based on the rate constant for ADP release and ADP affinity for actin-myosin. All three FSS mutations show dramatic changes in kinetic properties, most notably the slowing of the apparent ATP hydrolysis step (reduced 5–9-fold), leading to a longer lived detached state and a slowed V max of the ATPase (2–35-fold), indicating a slower cycling time. These mutations therefore seriously disrupt myosin function.

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          Most cited references 42

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          The SWISS-MODEL Repository and associated resources

          SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) is a database of 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms. Regular updates ensure that target coverage is complete, that models are built using the most recent sequence and template structure databases, and that improvements in the underlying modelling pipeline are fully utilised. As of September 2008, the database contains 3.4 million entries for 2.7 million different protein sequences from the UniProt database. SWISS-MODEL Repository allows the users to assess the quality of the models in the database, search for alternative template structures, and to build models interactively via SWISS-MODEL Workspace (http://swissmodel.expasy.org/workspace/). Annotation of models with functional information and cross-linking with other databases such as the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base facilitates the navigation between protein sequence and structure resources.
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            Purification of muscle actin.

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              Structural and functional insights into the Myosin motor mechanism.

              The general structural features of the motor region of myosin superfamily members are now well established, as is a subset of the structural and kinetic transitions of the actin-myosin catalytic cycle. Not yet visualized are the structural rearrangements triggered by actin binding that are coupled to force generation and product release. In this review we describe the recent progress in understanding these missing components of the mechanism of chemomechanical transduction by myosin motors. These insights come from a combination of kinetic and single-molecule studies on multiple classes of myosins, with additional insights from contracting muscle fibers. These recent studies have explored the effects of intermediate and high loads on the kinetics of the actin-bound myosin state transitions. We also describe studies that delineate how some classes of myosin motors are adapted for processive movement on actin.

                Author and article information

                J Biol Chem
                J. Biol. Chem
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                6 May 2016
                4 March 2016
                4 March 2016
                : 291
                : 19
                : 10318-10331
                From the []School of Biosciences, University of Kent, Canterbury CT2 7NJ, United Kingdom and
                the [§ ]Department of Molecular and Developmental Biology, University of Colorado, Boulder, Colorado 80309
                Author notes
                [2 ] To whom correspondence may be addressed. Tel.: 44-1227-827597; E-mail: M.A.Geeves@ 123456kent.ac.uk .
                [3 ] To whom correspondence may be addressed. Tel.: 303-492-7606; E-mail: leslie.leinwand@ 123456Colorado.edu .

                Present address: Biomolecular Research Group, School of Human and Life Sciences, Canterbury Christ Church University, Canterbury CT1 1QU, United Kingdom.

                © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version free via Creative Commons CC-BY license.

                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: GM29090
                Funded by: Wellcome Trust http://dx.doi.org/10.13039/100004440
                Award ID: 085309
                Molecular Bases of Disease


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