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J. Biol. Chem., Vol. 279, Issue 30, 31697-31707, July 23, 2004

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Identification of Functional Residues on Caenorhabditis elegans Actin-interacting Protein 1 (UNC-78) for Disassembly of Actin Depolymerizing Factor/Cofilin-bound Actin Filaments^*

Kurato Mohri, Sergeui Vorobiev¶||, Alexander A. Fedorov¶, Steven C. Almo¶**, and Shoichiro Ono

From the Department of Pathology, Emory University, Atlanta, Georgia 30322, Departments of ^¶Biochemistry and ^**Physiology and Biophysics, and Center for Synchrotron Biosciences, Albert Einstein College of Medicine, Bronx, New York 10461

Actin-interacting protein 1 (AIP1) is a WD40 repeat protein that enhances actin filament disassembly in the presence of actin-depolymerizing factor (ADF)/cofilin. AIP1 also caps the barbed end of ADF/cofilin-bound actin filament. However, the mechanism by which AIP1 interacts with ADF/cofilin and actin is not clearly understood. We determined the crystal structure of Caenorhabditis elegans AIP1 (UNC-78), which revealed 14 WD40 modules arranged in two seven-bladed -propeller domains. The structure allowed for the mapping of conserved surface residues, and mutagenesis studies identified five residues that affected the ADF/cofilin-dependent actin filament disassembly activity. Mutations of these residues, which reside in blades 3 and 4 in the N-terminal propeller domain, had significant effects on the disassembly activity but did not alter the barbed end capping activity. These data support a model in which this conserved surface of AIP1 plays a direct role in enhancing fragmentation/depolymerization of ADF/cofilin-bound actin filaments but not in barbed end capping.

Received for publication, March 25, 2004 , and in revised form, May 6, 2004.

The atomic coordinates and structure factors (codes 1NR0 and 1PEV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institute of Health Grant GM53807 (to S. C. A.) and National Science Foundation Grant MCB-0110464 (to S. O.). The X9B beamline is supported by Technology Centers Program of the National Institute for Biological Imaging and Bioengineering Grant P41-EB-01979. The National Synchrotron Light Source at Brookhaven National Laboratory is supported by the Department of Energy, Division of Materials Sciences. 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 two additional figures.

These authors contributed equally to this work.

^|| Present address: Dept. of Biological Sciences, Columbia University, New York, NY 10027.

To whom correspondence should be addressed: Dept. of Pathology, Emory University, 615 Michael St., Whitehead Research Bldg., Rm. 105N, Atlanta, GA 30322. Tel.: 404-727-3916; Fax: 404-727-8538; E-mail: sono{at}emory.edu.

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