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000137990 0247_ $$2doi$$a10.1042/BSR20150042
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000137990 0247_ $$2ISSN$$a1573-4935
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000137990 041__ $$aEnglish
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000137990 1001_ $$0P:(DE-HGF)0$$aHaslbeck, Veronika$$b0
000137990 245__ $$aSelective activators of protein phosphatase 5 target the auto-inhibitory mechanism.
000137990 260__ $$aColchester$$bPortland Press$$c2015
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000137990 520__ $$aProtein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase. Its dephosphorylation activity modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau protein involved in neurodegenerative disorders. It is auto-regulated by its heat-shock protein (Hsp90)-interacting tetratricopeptide repeat (TPR) domain and its C-terminal α-helix. In the present study, we report the identification of five specific PP5 activators [PP5 small-molecule activators (P5SAs)] that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating efficiently the turnover rate of PP5, but do barely affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Enzymatic studies imply that the compounds bind to the phosphatase domain of PP5. For the most promising compound crystallographic comparisons of the apo PP5 and the PP5-P5SA-2 complex indicate a relaxation of the auto-inhibited state of PP5. Residual electron density and mutation analyses in PP5 suggest activator binding to a pocket in the phosphatase/TPR domain interface, which may exert regulatory functions. These compounds thus may expose regulatory mechanisms in the PP5 enzyme and serve to develop optimized activators based on these scaffolds.
000137990 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000137990 542__ $$2Crossref$$i2019-07-25$$uhttp://creativecommons.org/licenses/by/3.0/
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000137990 650_7 $$2NLM Chemicals$$aCaenorhabditis elegans Proteins
000137990 650_7 $$2NLM Chemicals$$aHSC70 Heat-Shock Proteins
000137990 650_7 $$2NLM Chemicals$$aNuclear Proteins
000137990 650_7 $$2NLM Chemicals$$aSmall Molecule Libraries
000137990 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aPhosphoprotein Phosphatases
000137990 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aprotein phosphatase 5
000137990 650_2 $$2MeSH$$aAnimals
000137990 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: metabolism
000137990 650_2 $$2MeSH$$aCrystallography, X-Ray
000137990 650_2 $$2MeSH$$aDrug Evaluation, Preclinical: methods
000137990 650_2 $$2MeSH$$aEnzyme Activation: drug effects
000137990 650_2 $$2MeSH$$aHSC70 Heat-Shock Proteins: genetics
000137990 650_2 $$2MeSH$$aHSC70 Heat-Shock Proteins: metabolism
000137990 650_2 $$2MeSH$$aMutation
000137990 650_2 $$2MeSH$$aNuclear Magnetic Resonance, Biomolecular
000137990 650_2 $$2MeSH$$aNuclear Proteins: antagonists & inhibitors
000137990 650_2 $$2MeSH$$aNuclear Proteins: chemistry
000137990 650_2 $$2MeSH$$aNuclear Proteins: metabolism
000137990 650_2 $$2MeSH$$aPhosphoprotein Phosphatases: antagonists & inhibitors
000137990 650_2 $$2MeSH$$aPhosphoprotein Phosphatases: chemistry
000137990 650_2 $$2MeSH$$aPhosphoprotein Phosphatases: metabolism
000137990 650_2 $$2MeSH$$aProtein Domains
000137990 650_2 $$2MeSH$$aRats
000137990 650_2 $$2MeSH$$aSmall Molecule Libraries: pharmacology
000137990 7001_ $$0P:(DE-HGF)0$$aDrazic, Adrian$$b1
000137990 7001_ $$0P:(DE-HGF)0$$aEckl, Julia M$$b2
000137990 7001_ $$0P:(DE-HGF)0$$aAlte, Ferdinand$$b3
000137990 7001_ $$0P:(DE-2719)9000898$$aHelmuth, Martin$$b4$$udzne
000137990 7001_ $$0P:(DE-HGF)0$$aPopowicz, Grzegorz$$b5
000137990 7001_ $$0P:(DE-HGF)0$$aSchmidt, Werner$$b6
000137990 7001_ $$0P:(DE-HGF)0$$aBraun, Frank$$b7
000137990 7001_ $$0P:(DE-HGF)0$$aWeiwad, Matthias$$b8
000137990 7001_ $$0P:(DE-HGF)0$$aFischer, Gunter$$b9
000137990 7001_ $$0P:(DE-HGF)0$$aGemmecker, Gerd$$b10
000137990 7001_ $$0P:(DE-HGF)0$$aSattler, Michael$$b11
000137990 7001_ $$0P:(DE-2719)9000420$$aStriggow, Frank$$b12
000137990 7001_ $$0P:(DE-HGF)0$$aGroll, Michael$$b13
000137990 7001_ $$0P:(DE-HGF)0$$aRichter, Klaus$$b14$$eCorresponding author
000137990 77318 $$2Crossref$$3journal-article$$a10.1042/bsr20150042$$b : Portland Press Ltd., 2015-06-01$$n3$$tBioscience Reports$$v35$$x0144-8463$$y2015
000137990 773__ $$0PERI:(DE-600)2014993-1$$a10.1042/BSR20150042$$gVol. 35, no. 3, p. e00210$$n3$$pe00210$$q35:3<e00210$$tBioscience reports$$v35$$x0144-8463$$y2015
000137990 8564_ $$uhttps://portlandpress.com/bioscirep/article/35/3/e00210/56684/Selective-activators-of-protein-phosphatase-5
000137990 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721540
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000137990 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9000898$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b4$$kDZNE
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