The Journal of Experimental Medicine
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Published 6 October 2003. doi:10.1084/jem.20022181
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© Rockefeller University Press, 0022-1007/2003/10/1077 $5.00
The Journal of Experimental Medicine, Volume 198, Number 7, 1077-1088

Targeting Platelet–Leukocyte Interactions : Identification of the Integrin Mac-1 Binding Site for the Platelet Counter Receptor Glycoprotein Ib{alpha}



Raila Ehlers1, Valentin Ustinov3, Zhiping Chen1, Xiaobin Zhang1, Ravi Rao2, F. William Luscinskas2, Jose Lopez4, Edward Plow3 and Daniel I. Simon1

1 Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115
2 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115
3 The Cleveland Clinic Foundation, Cleveland, OH 44195
4 Thrombosis Research Section, Departments of Medicine and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

Address correspondence to Daniel I. Simon, Brigham and Women's Hospital, Cardiovascular Division, 75 Francis Street, Tower 3, Boston, MA 02115. Phone: (617) 732-5867; Fax: (617) 732-5132; email: dsimon{at}rics.bwh.harvard.edu

The firm adhesion and transplatelet migration of leukocytes on vascular thrombus are dependent on the interaction of the leukocyte integrin Mac-1 ({alpha}Mß2, CD11b/CD18) and the platelet counter receptor glycoprotein (GP) Ib{alpha}. Previous studies have established a central role for the I domain, a stretch of ~200 amino acids within the {alpha}M subunit, in the binding of GP Ib{alpha}. This study was undertaken to establish the molecular basis of GP Ib{alpha} recognition by {alpha}Mß2. The P201–K217 sequence, which spans an exposed loop and amphipathic {alpha}4 helix in the three-dimensional structure of the {alpha}MI domain, was identified as the binding site for GP Ib{alpha}. Mutant cell lines in which the {alpha}MI domain segments P201–G207 and R208–K217 were switched to the homologous, but non-GP Ib{alpha} binding, {alpha}L domain segments failed to support adhesion to GP Ib{alpha}. Mutation of amino acid residues within P201–K217, H210–A212, T213–I215, and R216–K217 resulted in the loss of the binding function of the recombinant {alpha}MI domains to GP Ib{alpha}. Synthetic peptides duplicating the P201–K217, but not scrambled versions, directly bound GP Ib{alpha} and inhibited {alpha}Mß2-dependent adhesion to GP Ib{alpha} and adherent platelets. Finally, grafting critical amino acids within the P201–K217 sequence onto {alpha}L, converted {alpha}Lß2 into a GP Ib{alpha} binding integrin. Thus, the P201–K217 sequence within the {alpha}MI domain is necessary and sufficient for GP Ib{alpha} binding. These observations provide a molecular target for disrupting leukocyte–platelet complexes that promote vascular inflammation in thrombosis, atherosclerosis, and angioplasty-related restenosis.

Key Words: inflammation • leukocytes • platelets • adhesion • receptors


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