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Originally published In Press as doi:10.1074/jbc.M107021200 on September 13, 2001

J. Biol. Chem., Vol. 276, Issue 47, 44275-44283, November 23, 2001
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Amino Acid Residues in the alpha IIb Subunit That Are Critical for Ligand Binding to Integrin alpha IIbbeta 3 Are Clustered in the beta -Propeller Model*

Tetsuji KamataDagger §, Kenneth K. Tieu, Atsushi Irie, Timothy A. Springer, and Yoshikazu Takada§

From the Department of Cell Biology, the Scripps Research Institute, La Jolla, California 92037 and the  Department of Pathology, Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115

Several distinct regions of the integrin alpha IIb subunit have been implicated in ligand binding. To localize the ligand binding sites in alpha IIb, we swapped all 27 predicted loops with the corresponding sequences of alpha 4 or alpha 5. 19 of the 27 swapping mutations had no effect on binding to both fibrinogen and ligand-mimetic antibodies (e.g. LJ-CP3), suggesting that these regions do not contain major ligand binding sites. In contrast, swapping the remaining 8 predicted loops completely blocked ligand binding. Ala scanning mutagenesis of these critical predicted loops identified more than 30 discontinuous residues in repeats 2-4 and at the boundary between repeats 4 and 5 as critical for ligand binding. Interestingly, these residues are clustered in the predicted beta -propeller model, consistent with this model. Most of the critical residues are located at the edge of the upper face of the propeller, and several critical residues are located on the side of the propeller domain. None of the predicted loops in repeats 1, 6, and 7, and none of the four putative Ca2+-binding predicted loops on the lower surface of the beta -propeller were important for ligand binding. The results map an important ligand binding interface at the edge of the top and on the side of the beta -propeller toroid, centering on repeat 3.

* This work was supported by National Institutes of Health Grant GM49899 (to Y. T.) and HL48675 (to T. A. S.) and by Department of the Army Grant DAMD17-97-1-7105 (to T. K.). This is Publication 10888-VB from The Scripps Research Institute.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.

The atomic coordinates and the structure factors (code 1JX5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger Present address: Dept. of Anatomy, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160, Japan.

§ To whom correspondence may be addressed: Dept. of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: takada@scripps.edu or kamata@sc.itc.keio.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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