Crystal structure of ICAM-2 reveals a distinctive integrin recognition surface

Recognition by integrin proteins on the cell surface regulates the adhesive interactions between cells and their surroundings 1,2 . The structure of the 'I' domain that is found in some but not all integrins, has been determined 3,4 . However, the only integrin ligands for which structures are known, namely fibronectin and VCAM-1 (refs 5–7), are recognized by integrins that lack I domains. The intercellular adhesion molecules ICAM-1, 2 and 3 are, like VCAM-1, members of the immunoglobulin superfamily (IgSF), but they are recognized by an I domain-containing integrin, lymphocyte-function-associated antigen 1 (LFA-1, or CD 11 a/CD 18). Here we present the crystal structure of the extracellular region of ICAM-2. The glutamic acid residue at position 37 is critical for LFA-1 binding and is proposed to coordinate the Mg 2+ ion in the I domain; this Glu 37 is surrounded by a relatively flat recognition surface and lies in a β-strand, whereas the critical aspartic acid residue in VCAM-1 and fibronectin lie in protruding loops. This finding suggests that there are differences in the architecture of recognition sites between integrins that contain or lack I domains. A bend between domains 1 and 2 of ICAM-2 and a tripod-like arrangement of N -linked glycans in the membrane-proximal region of domain 2 may be important for presenting the recognition surface to LFA-1. A model of ICAM-1 based on the ICAM-2 structure provides a framework for understanding its recognition by pathogens.