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J. Biol. Chem., Vol. 280, Issue 9, 8324-8331, March 4, 2005

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Dual Function for a Unique Site within the ₂I Domain of Integrin _M2^*

Driss Ehirchiou, Yu-Mei Xiong, Yang Li, Shelesa Brew, and Li Zhang, An established investigator of the American Heart Association¶

From the Departments of Physiology and Biochemistry, University of Maryland School of Medicine, Rockville, Maryland 20855

Integrin activation has been postulated to occur in part via conformational changes in the I domain of the subunit (the I domain), especially near the F-₇ loop, in response to "inside-out" signaling. However, direct evidence for a role of the F-₇ loop in ligand binding and activity modulation is still lacking. Here, we report our finding that the F-₇ loop (residues 344–358) within the ₂I domain has dual functions in ligand binding by _M2. On the one hand, it supports intercellular adhesion molecule 1 (ICAM-1) binding to _M2 directly as part of a recognition interface formed by five noncontiguous segments (Pro¹⁹²–Glu¹⁹⁷, Asn²¹³–Glu²²⁰, Leu²²⁵–Leu²³⁰, Ser³²⁴–Thr³²⁹, and Glu³⁴⁴–Asp³⁴⁸) on the apex of the ₂I domain. On the other hand, it controls the open and closed conformation of the _M2 receptor, thereby indirectly affecting _M2 binding to other ligands. Switching the five constituent sequences of the ICAM-1-binding site within the ₂I domain to their ₁ counterparts destroyed ICAM-1 binding but had no effect on the gross conformations of the receptor. Of the five ICAM-1 binding-defective mutants, four had normal or even stronger interaction with Fg and C3bi, as reported in our previous study. Synthetic peptides derived from the identified site inhibited _M2-ICAM-1 interaction and supported direct binding to ICAM-1. Most importantly, perturbation of the F-₇ loop caused conformational changes within the ₂I domain, which was further propagated to other regions of _M2. Altogether, our data demonstrate that inside-out signaling could modulate ligand binding directly by changing the ligand-binding pocket per se and/or indirectly by inducing multiple conformational changes within the receptor.

Received for publication, December 1, 2004

^* This work was supported in part by NHLBI, National Institute of Health Grant R01 HL61589-01 and by American Heart Association Grant 0240208N. 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.

^¶ To whom correspondence should be addressed: Dept. of Physiology, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855. Tel.: 301-738-0657; Fax: 301-738-0465; E-mail: ZHANGL{at}USA.REDCROSS.ORG.

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