Skeletal muscle myosin light chains are essential for physiological speeds of shortening

Lowey, Susan; Waller, Guillermina S.; Trybus, Kathleen M.

doi:10.1038/365454a0

Cited by 303 publications

(234 citation statements)

References 18 publications

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“…A variety of mutational and light chain dissociation studies have suggested that an increase in the compliance of the lever arm yields a decrease in actin filament velocity (34,39,40). The slower contractile velocity of vertebrate smooth muscle relative to skeletal muscle (41) is probably due to numerous factors.…”

Section: Resultsmentioning

confidence: 99%

Visualizing key hinges and a potential major source of compliance in the lever arm of myosin

Brown

Kumar

O'Neall-Hennessey

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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We have determined the 2.3-Å-resolution crystal structure of a myosin light chain domain, corresponding to one type found in sea scallop catch ("smooth") muscle. This structure reveals hinges that may function in the "on" and "off" states of myosin. The molecule adopts two different conformations about the heavy chain "hook" and regulatory light chain (RLC) helix D. This conformational change results in extended and compressed forms of the lever arm whose lengths differ by 10 Å. The heavy chain hook and RLC helix D hinges could thus serve as a potential major and localized source of cross-bridge compliance during the contractile cycle. In addition, in one of the molecules of the crystal, part of the RLC N-terminal extension is seen in atomic detail and forms a oneturn alpha-helix that interacts with RLC helix D. This extension, whose sequence is highly variable in different myosins, may thus modulate the flexibility of the lever arm. Moreover, the relative proximity of the phosphorylation site to the helix D hinge suggests a potential role for conformational changes about this hinge in the transition between the on and off states of regulated myosins.protein crystal structure | light chain binding domain | glycine | regulation

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Section: Resultsmentioning

confidence: 99%

Visualizing key hinges and a potential major source of compliance in the lever arm of myosin

Brown

Kumar

O'Neall-Hennessey

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Removing MLCs from chicken skeletal muscle myosin reduces the velocity of actin filament movement by 90% in an in vitro motility assay (21). Furthermore, MLC2 removal has little effect on isometric force, whereas MLC1 removal reduces the isometric force by over 50% (22).…”

Section: Discussionmentioning

confidence: 99%

Essential myosin light chain as a target for caspase-3 in failing myocardium

Moretti

Weig

Ott

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Programmed cell death involves the activation of caspase proteases that can mediate the cleavage of vital cytoskeletal proteins. We have recently reported that, in failing cardiac myocytes, caspase-3 activation is associated with a reduction in contractile performance. In this study we used a modified yeast two-hybrid system to screen for caspase-3 interacting proteins of the cardiac cytoskeleton. We identified ventricular essential myosin light chain (vMLC1) as a target for caspase-3. By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE 135 G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. Adenoviral gene transfer of the caspase inhibitor p35 in vivo prevented caspase-3 activation and vMLC1 cleavage, with positive impact on contractility. These data suggest that direct cleavage of vMLC1 by activated caspase-3 may contribute to depression of myocyte function by altering cross-bridge interaction between myosin and actin molecules. Therefore, activation of apoptotic pathways in the heart may lead to contractile dysfunction before cell death.

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“…The ELC of vertebrate striated muscle exist in two isoforms: alkali 1 (A1)-like and alkali 2 (A2)-like (6,7), and the presence of one, or the other, isoform appears to fine tune the contractile properties of the myosin molecule carrying it. This effect has been demonstrated in single muscle fibers (8), in in vitro motility assays (9), and in enzyme assays (10), where experiments are generally carried out with the more biochemically amenable myosin subfragment 1 (S1, a soluble, proteolytic fragment of myosin that retains the actin binding and MgATPase activities of the intact molecule). S1 prepared by chymotryptic digestion carries only one ELC and a fragment of the heavy chain (10).…”

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confidence: 99%

Size and Charge Requirements for Kinetic Modulation and Actin Binding by Alkali 1-type Myosin Essential Light Chains

Timson¹,

Trayer

Smith

et al. 1999

Journal of Biological Chemistry

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Skeletal muscle myosin light chains are essential for physiological speeds of shortening

Cited by 303 publications

References 18 publications

Visualizing key hinges and a potential major source of compliance in the lever arm of myosin

Visualizing key hinges and a potential major source of compliance in the lever arm of myosin

Essential myosin light chain as a target for caspase-3 in failing myocardium

Size and Charge Requirements for Kinetic Modulation and Actin Binding by Alkali 1-type Myosin Essential Light Chains

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