Structural requirements for mucosal vascular addressin binding to its lymphocyte receptor alpha 4 beta 7. Common themes among integrin-Ig family interactions.
The mucosal vascular addressin, MAdCAM-1, is an Ig family adhesion receptor preferentially expressed by venular endothelial cells at sites of lymphocyte extravasation in mucosal lymphoid tissues and lamina propria. MAdCAM-1 binds the lymphocyte homing receptor for Peyer's patches, the integrin alpha 4 beta 7. We describe a point mutation within the first Ig domain of MAdCAM-1 that abolishes activation-independent alpha 4 beta 7 binding. This point mutation resides within an eight-amino acid motif with homology to sequences important for the integrin binding ability of the related vascular Ig family members, ICAM-1 and VCAM-1. To understand the contributions of the individual MAdCAM-1 domains, chimeric exchanges with the beta 1 integrin ligand, ICAM-1, were made. The two N-terminal domains of MAdCAM-1 are sufficient to confer alpha 4 beta 7 binding comparable to that of native MAdCAM-1. A chimera containing only the N-terminal Ig domain (domain 1) of MAdCAM-1 can also bind (to a lesser extent) alpha 4 beta 7, but only after integrin (to a lesser extent) alpha 4 beta 7, but only after integrin activation. Conversely, the first domain of ICAM-1 appears sufficient to bind activated LFA-1. These data suggest that the first domain of MAdCAM-1 is sufficient for interaction with alpha 4 beta 7, but that sequences within the second domain support this interaction, either by providing additional contact points for integrin binding or by contributing to the conformation or presentation of the N-terminal domain. The second domain of MAdCAM-1 can also support activation-dependent LFA-1 binding to domain 1 of ICAM-1. The findings parallel studies of VCAM-1 binding to alpha 4 beta 1 and suggest that structural differences exist between vascular Ig-like ligands for alpha 4 vs beta 2 integrins.
Department of Pathology, Stanford University School of Medicine, CA 94305-5324, USA.
M J
MJ
Briskin
L
L
Rott
E C
EC
Butcher
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D016466:CHO Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D016384:Consensus Sequence; D006224:Cricetinae; D003412:Cricetulus; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007413:Intestinal Mucosa / Q000098:blood supply*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013696:Temperature; D014162:Transfection; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C069886:L-selectin counter-receptors; D016169:Lymphocyte Function-Associated Antigen-1; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; C504268:Madcam1 protein, rat; D008565:Membrane Proteins; D009088:Mucoproteins; D011993:Recombinant Fusion Proteins; C071777:integrin alpha4beta7; D018799:Intercellular Adhesion Molecule-1