title: Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 A resolution.
abstract: 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.affiliation: Laboratory of Molecular Biophysics, Oxford Centre for Molecular Sciences, UK.
authors.forename: E Y
authors.initials: EY
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Harlos
authors.forename: M J
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: R C
authors.initials: RC
authors.lastname: Robinson
authors.forename: P C
authors.initials: PC
authors.lastname: Driscoll
authors.forename: R M
authors.initials: RM
authors.lastname: Edwards
authors.forename: J M
authors.initials: JM
authors.lastname: Clements
authors.forename: T J
authors.initials: TJ
authors.lastname: Dudgeon
authors.forename: D I
authors.initials: DI
authors.lastname: Stuart
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018801:CD2 Antigens / Q000737:chemistry / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016029:Receptors, Very Late Antigen / Q000378:metabolism*; D011994:Recombinant Proteins; D017386:Sequence Homology, Amino Acid; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D018801:CD2 Antigens; D015815:Cell Adhesion Molecules; D016029:Receptors, Very Late Antigen; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1