Role of ADMIDAS Cation-binding Site in Ligand Recognition by Integrin α5β1

A. Paul Mould, Stephanie J. Barton, Janet A. Askari, Susan E. Craig, Martin J. Humphries

    Research output: Contribution to journalArticlepeer-review


    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and multiple cation-binding sites are found in both α and β integrin subunits. A key cation-binding site that lies in the β subunit A-domain is known as the metal-ion dependent adhesion site (MIDAS). Recent x-ray crystal structures of integrin αvβ3 have identified a novel cation binding site in this domain, known as the ADMIDAS (adjacent to MIDAS). The role of this novel site in ligand recognition has yet to be elucidated. Using the interaction between α5β 1 and fibronectin as a model system, we show that mutation of residues that form the ADMIDAS site inhibits ligand binding but this effect can be partially rescued by the use of activating monoclonal antibodies. The ADMIDAS mutants had decreased expression of activation epitopes recognized by 12G10, 15/7, and HUTS-4, suggesting that the ADMIDAS is important for stabilizing the active conformation of the integrin. Consistent with this suggestion, the ADMIDAS mutations markedly increased the dissociation rate of the integrin-fibronectin complex. Mutation of the ADMIDAS residues also reduced the allosteric inhibition of Mn2+-supported ligand binding by Ca 2+, suggesting that the ADMIDAS is a Ca2+-binding site involved in the inhibition of Mn2+-supported ligand binding. Mutations of the ADMIDAS site also perturbed transduction of a conformational change from the MIDAS through the C-terminal helix region of the βA domain to the underlying hybrid domain, implying an important role for this site in receptor signaling.
    Original languageEnglish
    Pages (from-to)51622-51629
    Number of pages7
    JournalJournal of Biological Chemistry
    Issue number51
    Publication statusPublished - 19 Dec 2003


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