Structure and relationship to function

All three ICAMs are typical integral membrane glycoproteins and are members of the immunoglobulin gene superfamily base on sequence homology. The extracellular domains are composed of discrete immunoglobulin (Ig) domains of the C2 type comprised of seven antiparallel (3 strands which form two P sheets held together by at least one intradomain disulfide bond. The extracellular domains of both ICAM-1 and ICAM-3 contain five Ig domains, while ICAM-2 contains only two. The Ig domains are predicted to provide a stable, rigid structural framework, and electron microscopy of purified molecules shows that ICAM-1 and ICAM-3 are rod-shape molecules approximately 19 and 15 nm long, respectively. These dimensions are consistent with an end-to-end arrangement of the Ig domains. ICAM-1 has a characteristic bend between domains D3 and D4 that may represent an area of molecular flexibility that provides increased receptor accessibility to key binding sites located at the N-terminus. In both the native membrane-bound and shed forms, ICAM-1 can exist as a homodimer which has significantly greater binding to LFA-1 than the monomeric form.

Site-specific mutagenesis and domain deletion analyses have localized the receptor-binding sites on each ICAM. For binding to LFA-1, the primary site of contact appears to be the N-terminal domain (Dl) on each molecule, with some contribution from the penultimate domain D2. The binding site on ICAM-1 for human rhinoviruses is also located in domain Dl, perhaps reflecting the overall molecular accessibility of this domain as it is held above the cell mem brane by the rigid framework of the other Ig domains. In contrast, the binding site for Mac-1 on ICAM-1 is localized on domain D3, raising the possibility that LFA-1 and Mac-1 might bind simultaneously, or independently in a regulated manner.

See also: Adhesion molecules; Immunoglobulin gene superfamily; Integrins; Lymphocyte function-associated antigen 1 (LFA-1).

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