Publication Date:
2015-04-21
Description:
Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase that is autoregulated by its Hsp90-interacting tetratricopeptide repeat (TPR) domain and its C-terminal α‑helix. PP5-catalyzed dephosphorylation modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau-protein involved in neurodegenerative disorders. Here, we report the identification of five specific PP5 activators (P5SAs) that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating exclusively the turnover rate of PP5, but do not affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Functional studies imply a binding site in the phosphatase domain and crystallographic comparisons of the apo PP5 and the PP5:P5SA-2 complex indicate a relaxation of the autoinhibited state of PP5 upon activator binding to the phosphatase-TPR domain interface. Mutations in this site suppress the activatory potential of the ligands. Thus, these compounds may be able to target a regulatory pocket at the domain interface of the PP5 enzyme and serve as a starting point to develop optimized activators based on these scaffolds.
Print ISSN:
0144-8463
Electronic ISSN:
1573-4935
Topics:
Biology
,
Chemistry and Pharmacology
