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J. Biol. Chem., Vol. 283, Issue 47, 32870-32879, November 21, 2008

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Actin Binding by Hip1 (Huntingtin-interacting Protein 1) and Hip1R (Hip1-related Protein) Is Regulated by Clathrin Light Chain^*

Jeremy D. Wilbur, Chih-Ying Chen, Venus Manalo, Peter K. Hwang^¶, Robert J. Fletterick^¶, and Frances M. Brodsky¹

From the Graduate Program in Biophysics, the G. W. Hooper Foundation, Departments of Biopharmaceutical Sciences, Microbiology and Immunology, and Pharmaceutical Chemistry, and the ^¶Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143

The huntingtin-interacting protein family members (Hip1 and Hip1R in mammals and Sla2p in yeast) link clathrin-mediated membrane traffic to actin cytoskeleton dynamics. Genetic data in yeast have implicated the light chain subunit of clathrin in regulating this link. To test this hypothesis, the biophysical properties of mammalian Hip1 and Hip1R and their interaction with clathrin light chain and actin were analyzed. The coiled-coil domains (clathrin light chain-binding) of Hip1 and Hip1R were found to be stable homodimers with no propensity to heterodimerize in vitro. Homodimers were also predominant in vivo, accounting for cellular segregation of Hip1 and Hip1R functions. Coiled-coil domains of Hip1 and Hip1R differed in their stability and flexibility, correlating with slightly different affinities for clathrin light chain and more markedly with effects of clathrin light chain binding on Hip protein-actin interactions. Clathrin light chain binding induced a compact conformation of both Hip1 and Hip1R and significantly reduced actin binding by their THATCH domains. Thus, clathrin is a negative regulator of Hip-actin interactions. These observations necessarily change models proposed for Hip protein function.

Received for publication, April 15, 2008 , and in revised form, September 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM038093 (to F. M. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ To whom correspondence should be addressed: Hooper Foundation, Box 0552, University of California, 513 Parnassus Ave., San Francisco, CA 94143-0552. E-mail: frances.brodsky{at}ucsf.edu.

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