Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 A resolution.

Journal article

The cell-surface glycoprotein vascular cell adhesion molecule-1 (VCAM-1; ref. 1) mediates intercellular adhesion by specific binding to the integrin very-late antigen-4 (VLA-4, alpha 4 beta 1; ref. 3). VCAM-1, with the intercellular adhesion molecules ICAM-1, ICAM-2, ICAM-3 and the mucosal vascular addressin MAd-CAM-1, forms an integrin-binding subgroup of the immunoglobulin superfamily. In addition to their clinical relevance in inflammation, these molecules act as cellular receptors for viral and parasitic agents. The predominant form of VCAM-1 in vivo has an amino-terminal extracellular region comprising seven immunoglobulin-like domains. Functional studies have identified a conserved integrin-binding motif in domains 1 and 4, variants of which are present in the N-terminal domain of all members of the immunoglobulin superfamily subgroup. We report here the crystal structure of a VLA-4-binding fragment composed of the first two domains of VCAM-1. The integrin-binding motif (Q38IDSPL) is highly exposed and forms the N-terminal region of the loop between beta-strands C and D of domain 1. This motif exhibits a distinctive conformation which we predict will be common to all the integrin-binding IgSF molecules. These, and additional data, map VLA-4 binding to the face of the CFG beta-sheet, the surface previously identified as the site for intercellular adhesive interactions between members of the immunoglobulin superfamily.

Authors: Jones, E; Harlos, K; Bottomley, M; Robinson, R; Driscoll, P

• Publication status: Published
• Journal: Nature
• Volume: 373
• Issue: 6514
• Pages: 539-544
• Publication date: 1995-02-01
• DOI: 10.1038/373539a0
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Computer Graphics; Crystallography, X-Ray; Antigens, CD2; Vascular Cell Adhesion Molecule-1; Cell Adhesion Molecules; Humans; Mutagenesis; Binding Sites; Recombinant Proteins; Receptors, Very Late Antigen; Escherichia coli; Protein Conformation; Sequence Homology, Amino Acid; Amino Acid Sequence; Protein Structure, Secondary; Molecular Sequence Data