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J. Biol. Chem., Vol. 280, Issue 23, 21908-21914, June 10, 2005

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The Serine-rich Domain from Crk-associated Substrate (p130^cas) Is a Four-helix Bundle^*

Klára Briknarová, Fariborz Nasertorabi, Marnie L. Havert, Ericka Eggleston, David W. Hoyt, Chenglong Li¶, Arthur J. Olson¶, Kristiina Vuori, and Kathryn R. Ely||

From the Burnham Institute, La Jolla, California 92037, the Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352, and the ^¶Scripps Research Institute, La Jolla, California 92037

p130^cas (Crk-associated substrate) is a docking protein that is involved in assembly of focal adhesions and concomitant cellular signaling. It plays a role in physiological regulation of cell adhesion, migration, survival, and proliferation, as well as in oncogenic transformation. The molecule consists of multiple protein-protein interaction motifs, including a serine-rich region that is positioned between Crk and Src-binding sites. This study reports the first structure of a functional domain of Cas. The solution structure of the serine-rich region has been determined by NMR spectroscopy, demonstrating that this is a stable domain that folds as a four-helix bundle, a protein-interaction motif. The serine-rich region bears strong structural similarity to four-helix bundles found in other adhesion components like focal adhesion kinase, -catenin, or vinculin. Potential sites for phosphorylation and interaction with the 14-3-3 family of cellular regulators are identified in the domain and characterized by site-directed mutagenesis and binding assays. Mapping the degree of amino acid conservation onto the molecular surface reveals a patch of invariant residues near the C terminus of the bundle, which may represent a previously unidentified site for protein interaction.

Received for publication, February 3, 2005 , and in revised form, March 17, 2005.

^* This work was supported by California Breast Cancer Research Program Grant 81B-0187, NCI, National Institutes of Health, Grant CA71560, and also by USARMDC Predoctoral Fellowship DAMD17-01-0169 and a Swedish-American Foundation award (to F. N.). The Environmental Molecular Sciences Laboratory is a national scientific user facility sponsored by the United States Department of Energy Office of Biological and Environmental Research. 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 atomic coordinates and structure factors (code 1Z23) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence should be addressed: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3135; Fax: 858-646-3105; E-mail: ely{at}burnham.org.

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