LFA-1 BINDING-SITE IN ICAM-3 CONTAINS A CONSERVED MOTIF AND NONCONTIGUOUS AMINO-ACIDS

被引:36
作者
SADHU, C
LIPSKY, B
ERICKSON, HP
HAYFLICK, J
DICK, KO
GALLATIN, WM
STAUNTON, DE
机构
[1] ICOS CORP,BOTHELL,WA 98021
[2] DUKE UNIV,MED CTR,DURHAM,NC 27710
关键词
ICAM-3; LFA-1; LEUKOCYTE ADHESION; INTEGRIN;
D O I
10.3109/15419069409004453
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The intercellular adhesion molecule-3 (ICAM-3) is a counter receptor for the integrin LFA-1 that supports cell-cell adhesion dependent functions. ICAM-3 is a member of the immunoglobulin superfamily possessing five immunoglobulin-like domains. Here, we characterize the overall shape of ICAM-3 and the amino acid residues involved in binding LFA-1 and monoclonal antibodies (Mab). Electron microscopic observations show that ICAM-3 is predominantly a straight rod of 15 nm in length, suggesting a head to tail arrangement of the immunoglobulin-like domains. Six out of nine ICAM-3 Mab described blocked the interaction with LFA-1 to varying degrees. Domain assignment of blocking Mab epitopes and characterization of LFA-1-dependent cell adhesion to ICAM-3 mutants demonstrate that the amino-terminal domain of ICAM-3 interacts with LFA-1. A conserved amino acid motif including residues E37 and T38 form an integrin binding site (IBS) in ICAM-3. This motif has also been shown to function as an IBS in ICAM-1 and VCAM-1 and hence may form a common site of contact in all CAMs of this type. Other ICAM-3 residues critical to adhesive interactions, such as Q75, conserved in ICAM-1 and ICAM-2, but not VCAM-1, may confer specificity to LFA-1 binding. This residue, Q75, is predicted to locate in a model of ICAM-3 to the same site as RGD in the immunoglobulin-like domain of fibronectin that binds several integrins. This suggests an evolutionary relationship between ICAMs and fibronectin interactions with integrins.
引用
收藏
页码:429 / 440
页数:12
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