TY  - JOUR
AU  - Haslbeck, Veronika
AU  - Drazic, Adrian
AU  - Eckl, Julia M
AU  - Alte, Ferdinand
AU  - Helmuth, Martin
AU  - Popowicz, Grzegorz
AU  - Schmidt, Werner
AU  - Braun, Frank
AU  - Weiwad, Matthias
AU  - Fischer, Gunter
AU  - Gemmecker, Gerd
AU  - Sattler, Michael
AU  - Striggow, Frank
AU  - Groll, Michael
AU  - Richter, Klaus
TI  - Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism.
JO  - Bioscience reports
VL  - 35
IS  - 3
SN  - 0144-8463
CY  - Colchester
PB  - Portland Press
M1  - DZNE-2020-04312
SP  - e00210
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Crystallography, X-Ray
KW  - Drug Evaluation, Preclinical: methods
KW  - Enzyme Activation: drug effects
KW  - HSC70 Heat-Shock Proteins: genetics
KW  - HSC70 Heat-Shock Proteins: metabolism
KW  - Mutation
KW  - Nuclear Magnetic Resonance, Biomolecular
KW  - Nuclear Proteins: antagonists & inhibitors
KW  - Nuclear Proteins: chemistry
KW  - Nuclear Proteins: metabolism
KW  - Phosphoprotein Phosphatases: antagonists & inhibitors
KW  - Phosphoprotein Phosphatases: chemistry
KW  - Phosphoprotein Phosphatases: metabolism
KW  - Protein Domains
KW  - Rats
KW  - Small Molecule Libraries: pharmacology
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
KW  - HSC70 Heat-Shock Proteins (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Small Molecule Libraries (NLM Chemicals)
KW  - Phosphoprotein Phosphatases (NLM Chemicals)
KW  - protein phosphatase 5 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26182372
C2  - pmc:PMC4721540
DO  - DOI:10.1042/BSR20150042
UR  - https://pub.dzne.de/record/137990
ER  -