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Originally published In Press as doi:10.1074/jbc.M110242200 on March 5, 2002

J. Biol. Chem., Vol. 277, Issue 21, 18769-18776, May 24, 2002
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Delineation of the Key Amino Acids Involved in Neutrophil Inhibitory Factor Binding to the I-domain Supports a Mosaic Model for the Capacity of Integrin alpha Mbeta 2 to Recognize Multiple Ligands*

Valentin A. UstinovDagger and Edward F. Plow§

From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, and Department of Molecular Cardiology/NB50, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

To gain insight into the mechanism by which the alpha MI-domain of integrin alpha Mbeta 2 interacts with multiple and unrelated ligands, the identity of the neutrophil inhibitory factor (NIF) recognition site was sought. A systematic strategy in which individual amino acid residues within three previously implicated segments were changed to those in the alpha LI-domain, which is structurally very similar but does not bind NIF, was implemented. The capacity of the resulting mutants, expressed as glutathione S-transferase fusion proteins, to recognize NIF was assessed. These analyses ultimately identified Asp149, Arg151, Gly207, Tyr252, and Glu258 as critical for NIF binding. Cation binding, a function of the metal ion-dependent adhesion site (MIDAS) motif, was assessed by terbium luminescence to evaluate conformational perturbations induced by the mutations. All five mutants bound terbium with unaltered affinities. When the five residues were inserted into the alpha LI-domain, the chimera bound NIF with high affinity. Another ligand of alpha Mbeta 2, C3bi, which is known to use the same segments of the alpha MI-domain in engaging the receptor, failed to bind to the chimeric alpha LI-domain. Thus, the alpha MI-domain appears to present a mosaic of exposed amino acids within surface loops on its MIDAS face, and different ligands interact with different residues to attain high affinity binding.

* This work was supported in part by National Institutes of Health Grant HL 66197.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.

Dagger Supported by an American Heart Association postdoctoral fellowship from the Northeast Ohio Affiliate.

§ To whom correspondence should be addressed: Joseph J. Jacobs Center for Thrombosis and Vascular Biology and Dept. of Molecular Cardiology/NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-8200; Fax: 216-445-8204; E-mail: plowe@ccf.org.

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