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

E. Y. Jones, K. Harlos, M. J. Bottomley, R. C. Robinson, P. C. Driscoll, R. M. Edwards, J. M. Clements, T. J. Dudgeon, D. I. Stuart

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Abstract

THE cell-surface glycoprotein vascular cell adhesion molecule-1 (VCAM-1; ref. 1) mediates intercellular adhesion2 by specific binding to the integrin very-late antigen-4 (VLA-4, α4β1; 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 immuno-globulin superfamily. In addition to their clinical relevance in inflammation, these molecules act as cellular receptors for viral and parasitic agents2. The predominant form of VCAM-1 in vivo has an ammo-terminal extracellular region comprising seven immunoglobulin-like domains. Functional studies4-7 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 β-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 β-sheet, the surface previously identified8 as the site for intercellular adhesive interactions between members of the immunoglobulin superfamily.

Original languageEnglish
Pages (from-to)539-544
Number of pages6
JournalNature
Volume373
Issue number6514
DOIs
Publication statusPublished - Feb 9 1995
Externally publishedYes

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ASJC Scopus subject areas

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Cite this

Jones, E. Y., Harlos, K., Bottomley, M. J., Robinson, R. C., Driscoll, P. C., Edwards, R. M., Clements, J. M., Dudgeon, T. J., & Stuart, D. I. (1995). Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 Å resolution. Nature, 373(6514), 539-544. https://doi.org/10.1038/373539a0