The Hypertrophic Cardiomyopathy Myosin Mutation R453C Alters ATP Binding and Hydrolysis of Human Cardiac β-Myosin

Bloemink, Marieke J.; Deacon, John C.; Langer, Shelby L.; Vera, Carlos; Combs, Ariana C.; Leinwand, Leslie A.; Geeves, Michael A.

doi:10.1074/jbc.m113.511204

Cited by 56 publications

(68 citation statements)

References 39 publications

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“…Kobayashi et al, 2013;Lin et al, 1996;Mirza et al, 2005;Tobacman et al, 1999). More recent studies have used human β-cardiac myosin, where some specific differences in biochemical parameters were found compared with earlier nonhuman myosin studies (Bloemink et al, 2014;Deacon et al, 2012;Gupte et al, 2015;Sommese et al, 2013b). Regardless of the source of the mammalian myosin, however, the general paradigm holds true that HCM mutations in tropomyosin or troponin are sensitizers to Ca 2+ (e.g.…”

Section: + -Desensitizing Respectivelymentioning

confidence: 96%

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Spudich

Aksel

Bartholomew

et al. 2016

Journal of Experimental Biology

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Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental forcegenerating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

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Section: + -Desensitizing Respectivelymentioning

confidence: 96%

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Spudich

Aksel

Bartholomew

et al. 2016

Journal of Experimental Biology

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“…The structure was built from the crystal structure of scallop myosin II (PDB-ID:1KK8) using the human β-myosin sequence and is based on fig. 1 of Bloemink et al (2014).…”

Section: Human Myosin Isoformsmentioning

confidence: 99%

“…Currently, designing mutations in a sarcomeric myosin is possible, but expensive and very time consuming. In collaboration with the Leinwand laboratory at the University of Colorado, Boulder, and the Spudich laboratory at Stanford University, we have begun to look at some of these mutations in human β-cardiac myosin; for example, R453C associated with hypertrophic cardiomyopathy (Bloemink et al, 2014;Sommese et al, 2013). We have defined the rate and equilibrium constants of each of the steps in the cycle as shown in Fig.…”

Section: Human Myosin Isoformsmentioning

confidence: 99%

Myosin isoforms and the mechanochemical cross-bridge cycle

Walklate

Ujfalusi

Geeves

2016

Journal of Experimental Biology

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At the latest count the myosin family includes 35 distinct groups, all of which have the conserved myosin motor domain attached to a neck or lever arm, followed by a highly variable tail or cargo binding region. The motor domain has an ATPase activity that is activated by the presence of actin. One feature of the myosin ATPase cycle is that it involves an association/dissociation with actin for each ATP hydrolysed. The cycle has been described in detail for a large number of myosins from different classes. In each case the cycle is similar, but the balance between the different molecular events in the cycle has been altered to produce a range of very different mechanical activities. Myosin may spend most of the ATPase cycle attached to actin (high duty ratio), as in the processive myosin (e.g. myosin V) or the strain-sensing myosins (e.g. myosin 1c). In contrast, most muscle myosins spend 80% of their ATPase cycle detached from actin. Within the myosin IIs found in human muscle, there are 11 different sarcomeric myosin isoforms, two smooth muscle isoforms as well as three non-muscle isoforms. We have been exploring how the different myosin isoforms have adapted the cross-bridge cycle to generate different types of mechanical activity and how this goes wrong in inherited myopathies. The ideas are outlined here.

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“…For example, myosin subfragments such as S1 and heavy meromyosin (HMM), which lack all or a portion of the tail domain, can be studied using the A/M m assay. These subfragments are soluble and easier to express than full-length myosin and thus allow the study of the effects of mutations (7)(8)(9)(10)(11). In contrast, the M f /A assay requires myosin with a full-length tail domain, the C-terminal portion of which contains the structural requirements for self-assembly into filaments.…”

Section: Introductionmentioning

confidence: 99%

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

Brizendine

Sheehy

Alcala

et al. 2018

Biophysical Journal

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In vitro motility assays, where purified myosin and actin move relative to one another, are used to better understand the mechanochemistry of the actomyosin adenosine triphosphatase (ATPase) cycle. We examined the relationship between the relative velocity (V) of actin and myosin and the number of available myosin heads (N) or [ATP] for smooth (SMM), skeletal (SKM), and cardiac (CMM) muscle myosin filaments moving over actin as well as V from actin filaments moving over a bed of monomeric SKM. These data do not fit well to a widely accepted model that predicts that V is limited by myosin detachment from actin (d/t on ), where d equals step size and t on equals time a myosin head remains attached to actin. To account for these data, we have developed a mixed-kinetic model where V is influenced by both attachment and detachment kinetics. The relative contributions at a given V vary with the probability that a head will remain attached to actin long enough to reach the end of its flexible S2 tether. Detachment kinetics are affected by L/t on , where L is related to the tether length. We show that L is relatively long for SMM, SKM, and CMM filaments (59 ± 3 nm, 22 ± 9 nm, and 22 ± 2 nm, respectively). In contrast, L is shorter (8 ± 3 nm) when myosin monomers are attached to a surface. This suggests that the behavior of the S2 domain may be an important mechanical feature of myosin filaments that influences unloaded shortening velocities of muscle.

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The Hypertrophic Cardiomyopathy Myosin Mutation R453C Alters ATP Binding and Hydrolysis of Human Cardiac β-Myosin

Cited by 56 publications

References 39 publications

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

Myosin isoforms and the mechanochemical cross-bridge cycle

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

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