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    Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts

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    Tan_2019.pdf (1.696Mb)
    Issue Date
    2019-07-02
    Author
    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
    Metadata
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    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.
    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.
    URI
    http://hdl.handle.net/1808/30788
    DOI
    https://doi.org/10.1021/acs.biochem.9b00430
    Collections
    • Center for Computational Biology Scholarly Works [38]
    • Molecular Biosciences Scholarly Works [606]
    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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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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