SDS22 selectively recognizes and traps metal-deficient inactive PP1.
SDS22
crystal structure
inhibitor
metal binding
protein phosphatase 1 (PP1)
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
08 10 2019
08 10 2019
Historique:
pubmed:
25
9
2019
medline:
4
4
2020
entrez:
25
9
2019
Statut:
ppublish
Résumé
The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, is regulated by scores of regulatory proteins, including the highly conserved SDS22 protein. SDS22 has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and as an activator. Here, we integrate cellular, biophysical, and crystallographic studies to address this conundrum. We discovered that SDS22 selectively binds a unique conformation of PP1 that contains a single metal (M2) at its active site, i.e., SDS22 traps metal-deficient inactive PP1. Furthermore, we showed that SDS22 dissociation is accompanied by a second metal (M1) being loaded into PP1, as free metal cannot dissociate the complex and M1-deficient mutants remain constitutively trapped by SDS22. Together, our findings reveal that M1 metal loading and loss are essential for PP1 regulation in cells, which has broad implications for PP1 maturation, activity, and holoenzyme subunit exchange.
Identifiants
pubmed: 31548429
pii: 1908718116
doi: 10.1073/pnas.1908718116
pmc: PMC6789808
doi:
Substances chimiques
Metals
0
Nuclear Proteins
0
Saccharomyces cerevisiae Proteins
0
Phosphoprotein Phosphatases
EC 3.1.3.16
Protein Phosphatase 1
EC 3.1.3.16
SDS22 protein, S cerevisiae
EC 3.1.3.16
Banques de données
PDB
['6OBN', '6OBP', '6OBQ', '6OBR', '6OBS', '6OBU']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
20472-20481Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM098482
Pays : United States
Organisme : NIBIB NIH HHS
ID : P30 EB009998
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM134683
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM111244
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103393
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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