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J. Biol. Chem., Vol. 283, Issue 50, 35154-35163, December 12, 2008

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Structural Basis of the Migfilin-Filamin Interaction and Competition with Integrin β Tails^*

Yatish Lad¹, Pengju Jiang¹², Salla Ruskamo^¶13, David S. Harburger⁴, Jari Ylänne^¶, Iain D. Campbell, and David A. Calderwood⁵

From the Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06520, the Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom, and the ^¶Department of Biological and Environmental Science, University of Jyväskylä, FIN-40014 Jyväskylä, Finland

A link between sites of cell adhesion and the cytoskeleton is essential for regulation of cell shape, motility, and signaling. Migfilin is a recently identified adaptor protein that localizes at cell-cell and cell-extracellular matrix adhesion sites, where it is thought to provide a link to the cytoskeleton by interacting with the actin cross-linking protein filamin. Here we have used x-ray crystallography, NMR spectroscopy, and protein-protein interaction studies to investigate the molecular basis of migfilin binding to filamin. We report that the N-terminal portion of migfilin can bind all three human filamins (FLNa, -b, or -c) and that there are multiple migfilin-binding sites in FLNa. Human filamins are composed of an N-terminal actin-binding domain followed by 24 immunoglobulin-like (IgFLN) domains and we find that migfilin binds preferentially to IgFLNa21 and more weakly to IgFLNa19 and -22. The filamin-binding site in migfilin is localized between Pro⁵ and Pro¹⁹ and binds to the CD face of the IgFLNa21 β-sandwich. This interaction is similar to the previously characterized β7 integrin-IgFLNa21 interaction and migfilin and integrin β tails can compete with one another for binding to IgFLNa21. This suggests that competition between filamin ligands for common binding sites on IgFLN domains may provide a general means of modulating filamin interactions and signaling. In this specific case, displacement of integrin tails from filamin by migfilin may provide a mechanism for switching between different integrin-cytoskeleton linkages.

Received for publication, April 3, 2008 , and in revised form, September 9, 2008.

The atomic coordinates and structure factors (code 2W0P) 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, in whole or in part, by National Institutes of Health Grant GM068600 (to D. A. C.). This work was also supported by Academy of Finland Grant 114713 (to J. Y.). 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 Fig. S1.

¹ These authors contributed equally to this work.

² Supported by Biotechnology and Biological Sciences Research Council Grant BB/F006845/1.

³ Supported by the Finnish Graduate School in Informational and Structural Biology.

⁴ Supported by a National Science Foundation Graduate Research Fellowship Award.

⁵ To whom correspondence should be addressed: Dept. of Pharmacology, Yale University School of Medicine, 333 Cedar St., P.O. Box 208066, New Haven, CT 06520-8066. Tel.: 203-737-2311; Fax: 203-785-7670; E-mail: david.calderwood{at}yale.edu.

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