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.
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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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