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J Biol Chem, Vol. 274, Issue 19, 13167-13175, May 7, 1999

Multiple Activation States of Integrin alpha 4beta 1 Detected through Their Different Affinities for a Small Molecule Ligand

Ling Ling Chen, Adrian Whitty, Roy R. Lobb, Steven P. Adams, and R. Blake Pepinsky

From Biogen, Inc., Cambridge, Massachusetts 02142

We have used the highly specific alpha 4beta 1 inhibitor 4-((N'-2-methylphenyl)ureido)-phenylacetyl-leucine-aspartic acid-valine-proline (BIO1211) as a model LDV-containing ligand to study alpha 4beta 1 integrin-ligand interactions on Jurkat cells under diverse conditions that affect the activation state of alpha 4beta 1. Observed KD values for BIO1211 binding ranged from a value of 20-40 nM in the non-activated state of the integrin that exists in 1 mM Mg2+, 1 mM Ca2+ to 100 pM in the activated state seen in 2 mM Mn2+ to 18 pM when binding was measured after co-activation by 2 mM Mn2+ plus 10 µg/ml of the integrin-activating monoclonal antibody TS2/16. The large range in KD values was governed almost exclusively by differences in the dissociation rates of the integrin-BIO1211 complex, which ranged from 0.17 × 10-4 s-1 to >140 × 10-4 s-1. Association rate constants varied only slightly under the same conditions, all falling in the narrow range from 0.9 to 2.7 × 106 M-1 s-1. The further increase in affinity observed upon co-activation by divalent cations and TS2/16 compared with that observed at saturating concentrations of metal ions or TS2/16 alone indicates that the mechanism by which these factors bring about activation are distinct and identified a previously unrecognized high affinity state on alpha 4beta 1 that had not been detected by conventional assay methods. Similar changes in affinity were observed when the binding properties of vascular cell adhesion molecule-1 and CS1 to alpha 4beta 1 were studied, indicating that the different affinity states detected with BIO1211 are an inherent property of the integrin.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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