THE STRUCTURE OF THE 2 AMINO-TERMINAL DOMAINS OF HUMAN ICAM-1 SUGGESTS HOW IT FUNCTIONS AS A RHINOVIRUS RECEPTOR AND AS AN LFA-1 INTEGRIN LIGAND

The normal function of human intercellular adhesion molecule-1 (ICAM-1 ) is to provide adhesion between endothelial cells and leukocytes afte r injury or stress. ICAM-1 binds to leukocyte function-associated anti gen (LFA-1) or macrophage-1 antigen (Mac-1). However, ICAM-1 is also u sed as a receptor by the major group of human rhinoviruses and is a ca talyst for the subsequent viral uncoating during cell entry. The three -dimensional atomic structure of the two amino-terminal domains (D1 an d D2) of ICAM-1 has been determined to 2.2-Angstrom resolution and fit ted into a cryoelectron microscopy reconstruction of a rhinovirus-ICAM -1 complex. Rhinovirus attachment is confined to the BC, CD, DE, and F G loops of the amino-terminal Ig-like domain (D1) at the end distal to the cellular membrane. The loops are considerably different in struct ure to those of human ICAM-2 or murine ICAM-1, which do not bind rhino viruses. There are extensive charge interactions beta een ICAM-1 and h uman rhinoviruses, which are mostly conserved in both major and minor receptor groups of rhinoviruses. The interaction of ICAMs with LFA-1 i s known to be mediated by a divalent cation bound to the insertion (I) -domain on the alpha chain of LFA-1 and the carboxyl group of a conser ved glutamic acid residue on ICAMs. Domain D1 has been docked with the known structure of the I-domain. The resultant model is consistent wi th mutational data and provides a structural framework for the adhesio n between these molecules.