Selective activators of protein phosphatase 5 target the autoinhibitory mechanism
| Autor: | Gerd Gemmecker, Martin Helmuth, Julia M. Eckl, Michael Groll, Werner Schmidt, Gunter Fischer, Matthias Weiwad, Ferdinand Alte, Adrian Drazic, Veronika Haslbeck, Frank Striggow, Klaus Richter, Frank Braun, Michael Sattler, Grzegorz M Popowicz |
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| Rok vydání: | 2015 |
| Předmět: |
metabolism [Caenorhabditis elegans Proteins]
Phosphatase Allosteric regulation Biophysics pharmacology [Small Molecule Libraries] Drug Evaluation Preclinical DUSP6 chemistry [Nuclear Proteins] Crystallography X-Ray Biochemistry genetics [HSC70 Heat-Shock Proteins] Dephosphorylation Small Molecule Libraries Protein Domains Modulation Of Phosphatase Activity Protein Phosphatase 5 Small-molecular Activators Phosphoprotein Phosphatases Animals protein phosphatase 5 Caenorhabditis elegans Proteins Molecular Biology Nuclear Magnetic Resonance Biomolecular metabolism [HSC70 Heat-Shock Proteins] metabolism [Phosphoprotein Phosphatases] small-molecular activators Original Paper biology Activator (genetics) antagonists & inhibitors [Phosphoprotein Phosphatases] HSC70 Heat-Shock Proteins Nuclear Proteins Cell Biology Protein phosphatase 2 Original Papers modulation of phosphatase activity Rats ddc Enzyme Activation Tetratricopeptide Chaperone (protein) ddc:540 Mutation biology.protein antagonists & inhibitors [Nuclear Proteins] chemistry [Phosphoprotein Phosphatases] methods [Drug Evaluation Preclinical] drug effects [Enzyme Activation] metabolism [Nuclear Proteins] |
| Zdroj: | Bioscience Reports Bioscience reports 35(3), e00210 (2015). doi:10.1042/BSR20150042 Biosci. Rep. 35:e00210 (2015) |
| Popis: | This paper describes the identification of compounds, which stimulate the activity of the protein phosphatase PPH-5 and addresses the influence of the identified compounds on the enzymatic properties and the potential mechanism of their action. Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase. Its dephosphorylation activity modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau protein involved in neurodegenerative disorders. It is auto-regulated by its heat-shock protein (Hsp90)-interacting tetratricopeptide repeat (TPR) domain and its C-terminal α-helix. In the present study, we report the identification of five specific PP5 activators [PP5 small-molecule activators (P5SAs)] that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating efficiently the turnover rate of PP5, but do barely affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Enzymatic studies imply that the compounds bind to the phosphatase domain of PP5. For the most promising compound crystallographic comparisons of the apo PP5 and the PP5–P5SA-2 complex indicate a relaxation of the auto-inhibited state of PP5. Residual electron density and mutation analyses in PP5 suggest activator binding to a pocket in the phosphatase/TPR domain interface, which may exert regulatory functions. These compounds thus may expose regulatory mechanisms in the PP5 enzyme and serve to develop optimized activators based on these scaffolds. |
| Databáze: | OpenAIRE |
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