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Originally published In Press as doi:10.1074/jbc.M208877200 on October 10, 2002

J. Biol. Chem., Vol. 277, Issue 50, 48635-48642, December 13, 2002
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A Molecular Basis for Integrin alpha Mbeta 2 Ligand Binding Promiscuity*

Valentin P. YakubenkoDagger , Valeryi K. LishkoDagger , Stephen C.-T. Lam§, and Tatiana P. UgarovaDagger

From the Dagger  Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and § Department of Pharmacology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612

The leukocyte integrin alpha Mbeta 2 is a highly promiscuous leukocyte receptor capable of binding a multitude of unrelated ligands. To understand the molecular basis for the broad ligand recognition of alpha Mbeta 2, the inter-integrin chimera was created. In the chimeric integrin, the beta D-alpha 5 loop-alpha 5 helix segment comprised of residues Lys245-Arg261 from the alpha MI domain of alpha Mbeta 2 was inserted into the framework of alpha Lbeta 2. The construct was expressed in HEK 293 cells, and the ability of generated cells to adhere to fibrinogen and its derivatives was characterized first. Grafting the alpha M(Lys245-Arg261) sequence converted alpha Lbeta 2 into a fibrinogen-binding protein capable of mediating efficient and specific adhesion similar to that of wild-type alpha Mbeta 2. Verifying a switch in the binding specificity of alpha Lbeta 2, the chimeric receptor became competent to support cell migration to fibrinogen. Mutations at positions Phe246, Asp254, and Pro257 within Lys245-Arg261 of alpha Mbeta 2 produced significant decreases in cell adhesion, illustrating the critical role of these residues in ligand binding. The insertion of alpha M(Lys245-Arg261) imparted to the chimeric integrin the ability to recognize many typical alpha Mbeta 2 protein ligands. Furthermore, cells expressing the chimeric receptor, but not alpha Lbeta 2, were able to stick to uncoated plastic, which represents the hallmark of wild-type alpha Mbeta 2. These results suggest that alpha M(Lys245-Arg261) serves as a consensus binding site for interaction with a variety of distinct molecules and, thus, may define the degenerate recognition properties inherent to alpha Mbeta 2.

* This work was supported by National Institutes of Health Grants HL 63199 (to T. P. U.) and HL 41793 (to S. C.-T. L.) and was performed during the tenure of an Established Investigatorship of the American Heart Association (to T. P. U.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Mail code NB 50, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Dept. of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Tel.: 216-445-8209; Fax: 216-445-8204; E-mail: ugarovt@ccf.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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