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Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism

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...

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Autores principales: Haslbeck, Veronika, Drazic, Adrian, Eckl, Julia M., Alte, Ferdinand, Helmuth, Martin, Popowicz, Grzegorz, Schmidt, Werner, Braun, Frank, Weiwad, Matthias, Fischer, Gunter, Gemmecker, Gerd, Sattler, Michael, Striggow, Frank, Groll, Michael, Richter, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721540/
https://www.ncbi.nlm.nih.gov/pubmed/26182372
http://dx.doi.org/10.1042/BSR20150042
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author Haslbeck, Veronika
Drazic, Adrian
Eckl, Julia M.
Alte, Ferdinand
Helmuth, Martin
Popowicz, Grzegorz
Schmidt, Werner
Braun, Frank
Weiwad, Matthias
Fischer, Gunter
Gemmecker, Gerd
Sattler, Michael
Striggow, Frank
Groll, Michael
Richter, Klaus
author_facet Haslbeck, Veronika
Drazic, Adrian
Eckl, Julia M.
Alte, Ferdinand
Helmuth, Martin
Popowicz, Grzegorz
Schmidt, Werner
Braun, Frank
Weiwad, Matthias
Fischer, Gunter
Gemmecker, Gerd
Sattler, Michael
Striggow, Frank
Groll, Michael
Richter, Klaus
author_sort Haslbeck, Veronika
collection PubMed
description 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.
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spelling pubmed-47215402016-02-02 Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism Haslbeck, Veronika Drazic, Adrian Eckl, Julia M. Alte, Ferdinand Helmuth, Martin Popowicz, Grzegorz Schmidt, Werner Braun, Frank Weiwad, Matthias Fischer, Gunter Gemmecker, Gerd Sattler, Michael Striggow, Frank Groll, Michael Richter, Klaus Biosci Rep Original Papers 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. Portland Press Ltd. 2015-06-22 /pmc/articles/PMC4721540/ /pubmed/26182372 http://dx.doi.org/10.1042/BSR20150042 Text en © 2015 Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0 (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Original Papers
Haslbeck, Veronika
Drazic, Adrian
Eckl, Julia M.
Alte, Ferdinand
Helmuth, Martin
Popowicz, Grzegorz
Schmidt, Werner
Braun, Frank
Weiwad, Matthias
Fischer, Gunter
Gemmecker, Gerd
Sattler, Michael
Striggow, Frank
Groll, Michael
Richter, Klaus
Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title_full Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title_fullStr Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title_full_unstemmed Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title_short Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
title_sort selective activators of protein phosphatase 5 target the auto-inhibitory mechanism
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721540/
https://www.ncbi.nlm.nih.gov/pubmed/26182372
http://dx.doi.org/10.1042/BSR20150042
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