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    Structural and functional basis of protein phosphatase 5 substrate specificity

    Oberoi, J. and Dunn, D. and Woodford, M. and Mariotti, L. and Schulman, J. and Bourboulia, D. and Mollapour, M. and Vaughan, Cara K. (2016) Structural and functional basis of protein phosphatase 5 substrate specificity. Proceedings of the National Academy of Sciences of the United States of America 113 (32), pp. 9009-9014. ISSN 0027-8424.

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    The serine/threonine phosphatase protein phosphatase 5 (PP5) reg- ulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5- mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal struc- ture of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP–substrate interactions. Our data show that, despite a highly conserved structure, elements of substrate specificity are determined within the phosphatase catalytic domain itself. Structure-based mutations in vivo reveal that PP5-mediated dephosphorylation is required for kinase and steroid hormone receptor release from the chaperone complex. Finally, our data show that hyper- or hypoactivity of PP5 mutants increases Hsp90 binding to its inhibitor, suggesting a mechanism to enhance the efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors.


    Item Type: Article
    Keyword(s) / Subject(s): Hsp90, PP5, Cdc37, chaperone, phosphatase
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Cara Vaughan
    Date Deposited: 06 Sep 2016 10:18
    Last Modified: 02 Aug 2023 17:25


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