Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Moretti, A. et al.

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

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.[1]

References

Essential myosin light chain as a target for caspase-3 in failing myocardium. Moretti, A., Weig, H.J., Ott, T., Seyfarth, M., Holthoff, H.P., Grewe, D., Gillitzer, A., Bott-Flügel, L., Schömig, A., Ungerer, M., Laugwitz, K.L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]

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