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Regulation of Cell Adhesion by Affinity and Conformational Unbending of ₄₁ Integrin¹

Department of Pathology and Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131

Rapid activation of integrins in response to chemokine-induced signaling serves as a basis for leukocyte arrest on inflamed endothelium. Current models of integrin activation include increased affinity for ligand, molecular extension, and others. In this study, using real-time fluorescence resonance energy transfer to assess ₄₁ integrin conformational unbending and fluorescent ligand binding to assess affinity, we report at least four receptor states with independent regulation of affinity and unbending. Moreover, kinetic analysis of chemokine-induced integrin conformational unbending and ligand-binding affinity revealed conditions under which the affinity change was transient whereas the unbending was sustained. In a VLA-4/VCAM-1-specific myeloid cell adhesion model system, changes in the affinity of the VLA-4-binding pocket were reflected in rapid cell aggregation and disaggregation. However, the initial rate of cell aggregation increased 9-fold upon activation, of which only 2.5-fold was attributable to the increased affinity of the binding pocket. These data show that independent regulation of affinity and conformational unbending represents a novel and fundamental mechanism for regulation of integrin-dependent adhesion in which the increased affinity appears to account primarily for the increasing lifetime of the ₄₁ integrin/VCAM-1 bond, whereas the unbending accounts for the increased capture efficiency.

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 This work was supported by National Institutes of Health Grants EB02022 and HL56384 (to L.A.S.), Leukemia and Lymphoma Society Grant 7388-06 (to L.A.S.), and AI60036 (to T.B.).

² Address correspondence and reprint requests to Dr. Alexandre Chigaev, Department of Pathology, University of New Mexico HSC, Albuquerque, NM 87131. E-mail address: achigaev{at}salud.unm.edu or Dr. Larry A. Sklar, Department of Pathology, University of New Mexico HSC, Albuquerque, NM 87131. E-mail address: lsklar{at}salud.unm.edu

³ Abbreviations used in this paper: GPCR, G protein-coupled receptor; FPR, formyl peptide receptor; FRET, fluorescence resonance energy transfer; HSA, human serum albumin; MCF, mean channel fluorescence, equivalent of mean fluorescence intensity; PKC, protein kinase C; PLC, phospholipase C, CD106.

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