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Molecular and Cellular Biology, November 2009, p. 6046-6058, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00654-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Muscle Lim Protein Interacts with Cofilin 2 and Regulates F-Actin Dynamics in Cardiac and Skeletal Muscle{triangledown}

Vasiliki Papalouka,1 Demetrios A. Arvanitis,1 Elizabeth Vafiadaki,1 Manolis Mavroidis,2 Stavroula A. Papadodima,3 Chara A. Spiliopoulou,3 Dimitrios T. Kremastinos,4 Evangelia G. Kranias,1,5 and Despina Sanoudou1,6*

Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece,1 Cell Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece,2 Department of Forensic Medicine and Toxicology, Medical School, National and Kapodistrian University of Athens, Athens, Greece,3 Second Department of Cardiology, University of Athens, Attikon Hospital, Athens, Greece,4 Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, Ohio,5 Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece6

Received 20 May 2009/ Returned for modification 12 June 2009/ Accepted 4 August 2009

The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of striated myocyte function. Mutations in the corresponding genes have been directly associated with severe human cardiac and skeletal myopathies, and aberrant expression patterns have often been observed in affected muscles. Herein, we have investigated whether MLP and CFL2 are involved in common molecular mechanisms, which would promote our understanding of disease pathogenesis. We have shown for the first time, using a range of biochemical and immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, which includes part of the actin depolymerization domain. The MLP/CFL2 complex is stronger in moderately acidic (pH 6.8) environments and upon CFL2 phosphorylation, while it is independent of Ca2+ levels. This interaction has direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent F-actin depolymerization, with maximal depolymerization enhancement at an MLP/CFL2 molecular ratio of 2:1. Deregulation of this interaction by intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, or expression changes, as observed in a range of cardiac and skeletal myopathies, could impair F-actin depolymerization, leading to sarcomere dysfunction and disease.

* Corresponding author. Mailing address: Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, Athens 115-27, Greece. Phone: 30-210-6597055. Fax: 30-210-6597545. E-mail: dsanoudo{at}enders.tch.harvard.edu

{triangledown} Published ahead of print on 14 September 2009.

Molecular and Cellular Biology, November 2009, p. 6046-6058, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00654-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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