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 α-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.
Data availability
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Structure of the PP2C Phosphatase Domain and a Fragment of the Regulatory Domain of the Cell Fate Determinant SpoIIE from Bacillus SubtilisPublicly available at the RCSB Protein Data Bank (accession no: 5UCG).
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Structure of the Phosphatase Domain of the Cell Fate Determinant SpoIIE from Bacillus subtilis in a crystal form without domain swappingPublicly available at the RCSB Protein Data Bank (accession no: 5MQH).
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Structure of the Phosphatase Domain of the Cell Fate Determinant SpoIIE from Bacillus subtilisPublicly available at the RCSB Protein Data Bank (accession no: 3T91).
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CRYSTAL STRUCTURE OF THE HSLUV PROTEASE-CHAPERONE COMPLEXPublicly available at the RCSB Protein Data Bank (accession no: 1G3I).
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CRYSTAL STRUCTURE OF THE H. INFLUENZAE PROTEASE HSLV AT 1.9 A RESOLUTIONPublicly available at the RCSB Protein Data Bank (accession no: 1G3K).
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Crystal structure of RsbX in complex with manganese in space group P21Publicly available at the RCSB Protein Data Bank (accession no: 3W43).
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Structure of Orthorhombic crystal form of Pseudomonas aeruginosa RssBPublicly available at the RCSB Protein Data Bank (accession no: 3F7A).
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Crystal structure of pyruvate dehydrogenase phosphatase 1 (PDP1)Publicly available at the RCSB Protein Data Bank (accession no: 2PNQ).
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Structure of a C.elegans sex determining proteinPublicly available at the RCSB Protein Data Bank (accession no: 4JND).
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Crystal structure of SnRK2.6 in complex with HAB1Publicly available at the RCSB Protein Data Bank (accession no: 3UJG).
Article and author information
Author details
Funding
National Institutes of Health (GM18568)
- Richard Losick
Wellcome (82829)
- Anthony J Wilkinson
Damon Runyon Cancer Research Foundation (DRG 2051-10)
- Niels Bradshaw
Jane Coffin Childs Memorial Fund for Medical Research
- Christina M Zimanyi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Bradshaw et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
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