Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts

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Issue Date
2019-07-02Author
Tan, Sophia K.
Fong, Karen P.
Polizzi, Nicholas F.
Sternisha, Alex
Slusky, Joanna S. G.
Yoon, Kyungchul
DeGrado, William F.
Bennett, Joel S.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
Copyright © 2019 American Chemical Society
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Show full item recordAbstract
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.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.9b00430.
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Citation
Tan, S. K., Fong, K. P., Polizzi, N. F., Sternisha, A., Slusky, J., Yoon, K., DeGrado, W. F., & Bennett, J. S. (2019). Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts. Biochemistry, 58(30), 3251–3259. https://doi.org/10.1021/acs.biochem.9b00430
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