5HPE

Phosphatase domain of PP5 bound to a phosphomimetic Cdc37 substrate peptide

Summary for 5HPE

• Entry DOI: 10.2210/pdb5hpe/pdb
• Descriptor: Serine/threonine-protein phosphatase 5,Hsp90 co-chaperone Cdc37, MANGANESE (II) ION, COBALT HEXAMMINE(III), ... (4 entities in total)
• Functional Keywords: phosphatase domain, enzyme, substrate, phosphorylation, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 40200.90

Authors

Oberoi, J.,Mariotti, L.,Vaughan, C. (deposition date: 2016-01-20, release date: 2016-07-27, Last modification date: 2024-01-10)

Primary citation

Oberoi, J.,Dunn, D.M.,Woodford, M.R.,Mariotti, L.,Schulman, J.,Bourboulia, D.,Mollapour, M.,Vaughan, C.K.
Structural and functional basis of protein phosphatase 5 substrate specificity.
Proc.Natl.Acad.Sci.USA, 113:9009-9014, 2016

PubMed 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.

PubMed: 27466404
DOI: 10.1073/pnas.1603059113

Experimental method

X-RAY DIFFRACTION (2.27 Å)