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Intercellular Adhesion Molecule-3 Binding of Integrin _Lβ₂ Requires Both Extension and Opening of the Integrin Headpiece¹

School of Biological Sciences, Nanyang Technological University, Singapore

The leukocyte-restricted integrin _Lβ₂ is required in immune processes such as leukocyte adhesion, migration, and immune synapse formation. Activation of _Lβ₂ by conformational changes promotes _Lβ₂ binding to its ligands, ICAMs. It was reported that different affinity states of _Lβ₂ are required for binding ICAM-1 and ICAM-3. Recently, the bent, extended with a closed headpiece, and extended with open headpiece conformations of _Lβ₂, was reported. To address the overall conformational requirements of _Lβ₂ that allow selective binding of these ICAMs, we examined the adhesion properties of these _Lβ₂ conformers. _Lβ₂ with different conformations were generated by mutations, and verified by using a panel of reporter mAbs that detect _Lβ₂ extension, hybrid domain movement, or I-like domain activation. We report a marked difference between extended _Lβ₂ with closed and open headpieces in their adhesive properties to ICAM-1 and ICAM-3. Our data show that the extension of _Lβ₂ alone is sufficient to mediate ICAM-1 adhesion. By contrast, an extended _Lβ₂ with an open headpiece is required for ICAM-3 adhesion.

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 study was supported by the Singapore A*STAR BMRC Grant 06/1/22/19/445. X.-Y.T. and Y.-F.L. performed the experiments; X.-Y.T. and S.-M.T. analyzed the results and made the figures; and S.-M.T. designed the study and wrote the paper.

² Address correspondence and reprint requests to Dr. Suet-Mien Tan, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. E-mail address: smtan{at}ntu.edu.sg

³ Abbreviations used in this paper: LAD, leukocyte adhesion deficiency; FRET, fluorescence resonance energy transfer; HI-FBS, heat-inactivated FBS; I-EGF, integrin epidermal growth factor; CFP, cyan fluorescent protein; YFP, yellow fluorescent protein; mCFP, monomeric CFP; mYFP, monomeric YFP; PNGase F, peptide N-glycosidase F.