Integrin Activation Involves a Conformational Change in the α1 Helix of the β Subunit A-domain*

By Paul Mould, J. Askari, S. Barton, A. Kline, P. McEwan, S. E. Craig, M. Humphries. Journal of Biological Chemistry, 2002

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The ligand-binding region of integrin β subunits contains a von Willebrand factor type A-domain: an α/β “Rossmann” fold containing a metal ion-dependent adhesion site (MIDAS) on its top face. Although there is evidence to suggest that the βA-domain undergoes changes in tertiary structure during receptor activation, the identity of the secondary structure elements that change position is unknown. The mAb 12G10 recognizes a unique cation-regulated epitope on the β1 A-domain, induction of which parallels the activation state of the integrin (i.e. competency for ligand recognition). The ability of Mn2+ and Mg2+ to stimulate 12G10 binding is abrogated by mutation of the MIDAS motif, demonstrating that the MIDAS is a Mn2+/Mg2+ binding site and that occupancy of this site induces conformational changes in the A-domain. The cation-regulated region of the 12G10 epitope maps to Arg154/Arg155 in the α1 helix. Our results demonstrate that the α1 helix undergoes conformational alterations during integrin activation and suggest that Mn2+ acts as a potent activator of β1integrins because it can promote a shift in the position of this helix. The mechanism of β subunit A-domain activation appears to be distinct from that of the A-domains found in some integrin α subunits.

Subfields: Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0422a322b8c9b1ff486496880a146e832eb89678

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