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J. Biol. Chem., Vol. 283, Issue 14, 9444-9453, April 4, 2008

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Control of the Ability of Profilin to Bind and Facilitate Nucleotide Exchange from G-actin^*

Kuo-Kuang Wen, Melissa McKane, Jon C. D. Houtman, and Peter A. Rubenstein¹

From the Departments of Biochemistry and Microbiology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

A major factor in profilin regulation of actin cytoskeletal dynamics is its facilitation of G-actin nucleotide exchange. However, the mechanism of this facilitation is unknown. We studied the interaction of yeast (YPF) and human profilin 1 (HPF1) with yeast and mammalian skeletal muscle actins. Homologous pairs (YPF and yeast actin, HPF1 and muscle actin) bound more tightly to one another than heterologous pairs. However, with saturating profilin, HPF1 caused a faster etheno-ATP exchange with both yeast and muscle actins than did YPF. Based on the -fold change in ATP exchange rate/K_d, however, the homologous pairs are more efficient than the heterologous pairs. Thus, strength of binding of profilin to actin and nucleotide exchange rate are not tightly coupled. Actin/HPF interactions were entropically driven, whereas YPF interactions were enthalpically driven. Hybrid yeast actins containing subdomain 1 (sub1) or subdomain 1 and 2 (sub12) muscle actin residues bound more weakly to YPF than did yeast actin (K_d = 2 µM versus 0.6 µM). These hybrids bound even more weakly to HPF than did yeast actin (K_d = 5 µM versus 3.2 µM). sub1/YPF interactions were entropically driven, whereas the sub12/YPF binding was enthalpically driven. Compared with WT yeast actin, YPF binding to sub1 occurred with a 5 times faster k_off and a 2 times faster k_on. sub12 bound with a 3 times faster k_off and a 1.5 times slower k_on. Profilin controls the energetics of its interaction with nonhybrid actin, but interactions between actin subdomains 1 and 2 affect the topography of the profilin binding site.

Received for publication, November 30, 2007 , and in revised form, January 24, 2008.

^* This work was supported in part by National Institutes of Health Grant GM33689 (to P. A. R.). 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.

¹ To whom correspondence should be addressed. Tel.: 319-335-7911; E-mail: peter-rubenstein{at}uiowa.edu.

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