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J. Biol. Chem., Vol. 280, Issue 4, 2879-2887, January 28, 2005

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Actin Activation of Myosin Heavy Chain Kinase A in Dictyostelium

A BIOCHEMICAL MECHANISM FOR THE SPATIAL REGULATION OF MYOSIN II FILAMENT DISASSEMBLY^*

Thomas T. Egelhoff, Daniel Croft, and Paul A. Steimle¶

From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and the Department of Biology, University of North Carolina, Greensboro, North Carolina 27402

Studies in Dictyostelium discoideum have established that the cycle of myosin II bipolar filament assembly and disassembly controls the temporal and spatial localization of myosin II during critical cellular processes, such as cytokinesis and cell locomotion. Myosin heavy chain kinase A (MHCK A) is a key enzyme regulating myosin II filament disassembly through myosin heavy chain phosphorylation in Dictyostelium. Under various cellular conditions, MHCK A is recruited to actin-rich cortical sites and is preferentially enriched at sites of pseudopod formation, and thus MHCK A is proposed to play a role in regulating localized disassembly of myosin II filaments in the cell. MHCK A possesses an aminoterminal coiled-coil domain that participates in the oligomerization, cellular localization, and actin binding activities of the kinase. In the current study, we show that the interaction between the coiled-coil domain of MHCK A and filamentous actin leads to an 40-fold increase in the initial rate of kinase catalytic activity. Actin-mediated activation of MHCK A involves increased rates of kinase autophosphorylation and requires the presence of the coiled-coil domain. Structure-function analyses revealed that the coiled-coil domain alone binds to actin filaments (apparent K_D = 0.9 µM) and thus mediates the direct interaction with F-actin required for MHCK A activation. Collectively, these results indicate that MHCK A recruitment to actin-rich sites could lead to localized activation of the kinase via direct interaction with actin filaments, and thus this mode of kinase regulation may represent an important mechanism by which the cell achieves localized disassembly of myosin II filaments required for specific changes in cell shape.

Received for publication, September 20, 2004 , and in revised form, November 8, 2004.

^* This work was supported by National Institutes of Health Grants 1R15GM066789-01A1 (to P. A. S.) and GM50009 (to T. T. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biology, 312 Eberhart Bldg., University of North Carolina, Greensboro, NC 27402. Tel.: 336-334-4949; Fax: 336-334-5839; E-mail: p_steiml{at}uncg.edu.

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