Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts.

ABSTRACT: Integrin αIIbβ3, a transmembrane heterodimer, mediates platelet aggregation when it switches from an inactive to an active ligand-binding conformation following platelet stimulation. Central to regulating αIIbβ3 activity is the interaction between the αIIb and β3 extracellular stalks, which form a tight heterodimer in the inactive state and dissociate in the active state. Here, we demonstrate that alanine replacements of sensitive positions in the heterodimer stalk interface destabilize the inactive conformation sufficiently to cause constitutive αIIbβ3 activation. To determine the structural basis for this effect, we performed a structural bioinformatics analysis and found that perturbing intersubunit contacts with favorable interaction geometry through substitutions to alanine quantitati

SUBMITTER: Tan SK 

PROVIDER: S-EPMC7405930 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature