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Structural and functional basis of protein phosphatase 5 substrate specificity

Oberoi, J; Dunn, DM; Woodford, MR; Mariotti, L; Schulman, J; Bourboulia, D; Mollapour, M; (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. 10.1073/pnas.1603059113. Green open access

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Abstract

The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates 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 structure 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.

Type: Article
Title: Structural and functional basis of protein phosphatase 5 substrate specificity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1603059113
Publisher version: http://dx.doi.org/10.1073/pnas.1603059113
Language: English
Additional information: Copyright © 2016 National Academy of Sciences.
Keywords: Hsp90, PP5, Cdc37, chaperone, phosphatase
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1508748
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