Analysis of the binding site on intercellular adhesion molecule 3 for the leukocyte integrin lymphocyte function-associated antigen 1.
Intercellular adhesion molecule 3 (ICAM-3, CD50) is a member of the immunoglobulin superfamily and is a constitutively expressed ligand for the leukocyte integrin LFA-1 (CD11a/CD18). ICAM-3 is expressed at high levels by all resting leukocyte populations and antigen presenting cells and is a major ligand for LFA-1 in the resting immune system. ICAM-3 is a signal transducer and may play a key role in initiating immune responses. Mutant ICAM-3 Fc-chimeric proteins were quantitatively analyzed for their ability to bind COS cells expressing human LFA-1. The LFA-1-binding site on ICAM-3 is located in the N-terminal 2 Ig domains. Domains 3-5 do not significantly contribute to adhesion. The binding site has been further resolved by rational targeting of 14 point mutations throughout domains 1 and 2, coupled with modeling studies. Within domain 1 a cluster of residues (Glu37, Leu66, Ser68, and Gln75), that are predicted to lie on the CC'FG face of the Ig fold, play a dominant role in LFA-1 binding.
Holness
C L
CL
Cell Adhesion Laboratory, John Radcliffe Hospital, Headington, Oxford, London, United Kingdom.
Bates
P A
PA
Little
A J
AJ
Buckley
C D
CD
McDowall
A
A
Bossy
D
D
Hogg
N
N
Simmons
D L
DL
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001483:Base Sequence; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017386:Sequence Homology, Amino Acid
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D017931:DNA Primers; C483616:ICAM3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1