Lymphocyte function-associated antigen-1 binding residues in intercellularadhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily

The crystal structure of intercellular adhesion molecule-2 (ICAM-2) reveale d significant differences in the presentation of the critical acidic residu e important for integrin binding between I and non-I-domain integrin ligand s, Based on this crystal structure, we mutagenized ICAM-2 to localize the b inding site for the integrin lymphocyte function-associated antigen-1 (LFA- I), The integrin binding site runs diagonally across the GFC beta-sheet and includes residues on the CD edge of the beta-sandwich. The site is oblong and runs along a flat ridge on the upper half of domain 1, which is propose d to dock to a groove in the I domain of LFA-1, with the critical Glu-37 re sidue ligating the Mg2+ in the I domain. Previous mutagenesis of ICAM-1 and ICAM-3, interpreted in light of the recently determined ICAM-1 and ICAM-2 structures, suggests similar binding sites. By contrast, major differences are seen with vascular cell adhesion molecule-1 (VCAM-1), which binds alpha (4) integrins that lack an I domain. The binding site on VCAM-1 includes th e lower portion of domain 1 and the upper part of domain 2, whereas the LFA -1 binding site on ICAM is confined to the upper part of domain 1.