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J. Biol. Chem., Vol. 283, Issue 16, 10642-10648, April 18, 2008

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A Mechanism for Antibody-mediated Outside-in Activation of LFA-1^*

Roberto Carreño¹, Dan Li, Mehmet Sen², Iris Nira¹, Tatsuo Yamakawa, Qing Ma, and Glen B. Legge³

From the Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001 and the Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

MEM83 is an inserted domain (I-domain)-specific antibody that up-regulates the interaction of LFA-1 with ICAM-1 through an outside-in activation mechanism. We demonstrate here that there is no change in the affinity of the MEM83 antibody for the I-domain in either its low (wild-type) or high affinity form and that MEM83 does not enhance the binding of the wild-type I-domain to ICAM-1. Furthermore, we show that the antibody acts as an activating agent to induce LFA-1/ICAM-1-dependent homotypic cell aggregation only as an IgG, but not as a Fab fragment. On the basis of these data, we propose an avidity-based mechanism that requires no direct activation of the LFA-1 I-domain by the binding of the antibody; rather, activation is enhanced when there is an interaction with both arms of the IgG. A molecular model of the antibody interaction with LFA-1 illustrates the symmetry and accessibility of the two MEM83 epitopes across the LFA-1/ICAM-1 heterotetramer. We hypothesize that MEM83 stabilizes adjacent LFA-1 molecules in their active form by the free energy that is gained from the binding of the I-domains to each arm of the IgG. This leads to stabilization of the open state of the integrin and outside-in signaling. Our model supports a mechanism in which both affinity and avidity regulation are required in the activation of LFA-1.

Received for publication, June 7, 2007 , and in revised form, January 11, 2008.

^* This work was supported in part by American Heart Foundation Grant 0435123N (to G. B. L.). 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.

¹ Recipients of research studentships from the Rice-Houston Alliance for Graduate Education and the Professoriate supported by National Science Foundation Grant 0450363.

² Present address: CBR Institute for Biomedical Research, Inc., Boston, MA 02115.

³ To whom correspondence should be addressed: Dept. of Biology and Biochemistry, University of Houston, 4800 Calhoun Rd., Houston, TX 77204-5001. Fax: 713-743-8351; E-mail: glegge{at}uh.edu.

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