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A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases.

ABSTRACT: PP2C phosphatases control biological processes including stress responses, development, and cell division in all kingdoms of life. Diverse regulatory domains adapt PP2C phosphatases to specific functions, but how these domains control phosphatase activity was unknown. We present structures representing active and inactive states of the PP2C phosphatase SpoIIE from Bacillus subtilis. Based on structural analyses and genetic and biochemical experiments, we identify an ?-helical switch that shifts a carbonyl oxygen into the active site to coordinate a metal cofactor. Our analysis indicates that this switch is widely conserved among PP2C family members, serving as a platform to control phosphatase activity in response to diverse inputs. Remarkably, the switch is shared with proteasomal proteases, which we identify as evolutionary and structural relatives of PP2C phosphatases. Although these proteases use an unrelated catalytic mechanism, rotation of equivalent helices controls protease activity by movement of the equivalent carbonyl oxygen into the active site.

SUBMITTER: Bradshaw N

PROVIDER: S-EPMC5468089 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases.

Bradshaw Niels N Levdikov Vladimir M VM Zimanyi Christina M CM Gaudet Rachelle R Wilkinson Anthony J AJ Losick Richard R

eLife 20170520

PP2C phosphatases control biological processes including stress responses, development, and cell division in all kingdoms of life. Diverse regulatory domains adapt PP2C phosphatases to specific functions, but how these domains control phosphatase activity was unknown. We present structures representing active and inactive states of the PP2C phosphatase SpoIIE from <i>Bacillus subtilis</i>. Based on structural analyses and genetic and biochemical experiments, we identify an α-helical switch that ...[more]

PMID: 28527238

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Project description:In all, 15 aryl-containing phosphonates have been synthesized and tested for their effect on protein-tyrosine phosphatase (PTPase) activity. Two compounds, (naphth-2-yl) difluoromethylphosphonic acid (12) and (napthy-1-yl) difluoromethylphosphonic acid (13) have been found to inhibit dephosphorylation of [32P]insulin receptors by PTP-1B, a protein tyrosine phosphatase (PTPase), with IC50 values of 40-50 microM. Compound 12 competitively inhibited insulin-receptor dephosphorylation by PTP-1B. Compound 12 also inhibited PTP-1B-catalysed dephosphorylation of a synthetic tyrosine phosphorylated substrate poly(Glu80-Tyr20) at the same potency, indicating that 12 acted via interaction with the PTPase. Additionally, 12 inhibited insulin-receptor PTPase(s) and epridermal-growth-factor-receptor PTPase(s) present in solubilized membranes from CHO (Chinese-hamster ovary)/HIRc and A431 cells respectively. IC50 values of 40-50 microM were obtained in all cases with compound 12. Of note is the fact that these compounds did not have any effect on insulin-receptor autophosphorylation. Nine out of the 15 compounds potently inhibited serine/threonine phosphatase PP-2A activity without any effect on serine/threonine phosphatase PP-1 when tested at a concentration as high as 675 microM. The most potent compounds acting toward PP-2A had IC50 values of 45-50 microM. These PP-2A inhibitors could be useful tools for studying serine/threonine-phosphatase-mediated signal transduction. Two compounds, 12 and 13, inhibited both tyrosine phosphatase PTP-1B and serine/threonine phosphatase PP-2A with similar potency; IC50 values being 40-50 microM in both cases. Details of the synthesis of compounds 10, 11 and 13 are given in Supplementary Publication SUP 50177 (6 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1995) 305, 9.

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A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases.

Publications

A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases.

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