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

By A. Mould, S. Barton, J. Askari, S. E. Craig, M. Humphries. Journal of Biological Chemistry, 2003

89 citations recorded by the source corpus.

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 α5β1 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 Ca2+, 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.

Subfields: Cancer Research, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/41468307664a63a29ea402bbb75fc4d5e9f41173

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology and Allergy

1. Iain D. Campbell
2. M. Humphries
3. C. Carman
4. B. Luo
5. T. Springer
6. Werner Müller
7. M. Schwartz

In Molecular Biology

1. M. Humphries
2. Iain D. Campbell
3. C. Carman
4. B. Luo
5. T. Springer
6. Werner Müller

Citations in the corpus

• Structural basis of integrin regulation and signaling. (2007, background): “Recent studies show that binding of metal ions to the LIMBS and ADMIDAS sites can explain these effects (49, 50).”
• Integrin structure, activation, and interactions. (2011, background): “Mutations that favor a downward shift of the a7 helix (Mould et al. 2003b; Hato et al. 2006; Cheng et al. 2007) also result in a high-affinity state.”