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 quantitatively accounted for the degree of constitutive αIIbβ3 activation. This mutational study directly assesses the relationship between favorable interaction geometry at mutation-sensitive positions and the functional activity of those mutants, giving rise to a simple model that highlights the importance of interaction geometry in contributing to the stability between protein-protein interactions.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Tan SK,Fong KP,Polizzi NF,Sternisha A,Slusky JSG,Yoon K,DeGrado WF,Bennett JSdoi
10.1021/acs.biochem.9b00430subject
Has Abstractpub_date
2019-07-30 00:00:00pages
3251-3259issue
30eissn
0006-2960issn
1520-4995journal_volume
58pub_type
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