Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition.
E. coli
P53
PME-1
biochemistry
chemical biology
demethylation
molecular biophysics
protein phosphatase 2A
short linear motifs
structural biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
04 08 2022
04 08 2022
Historique:
received:
25
04
2022
accepted:
03
08
2022
pubmed:
5
8
2022
medline:
26
8
2022
entrez:
4
8
2022
Statut:
epublish
Résumé
Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.
Identifiants
pubmed: 35924897
doi: 10.7554/eLife.79736
pii: 79736
pmc: PMC9398451
doi:
pii:
Substances chimiques
Holoenzymes
0
Protein Phosphatase 2
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM137090
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM096060
Pays : United States
Déclaration de conflit d'intérêts
YL, VB, MR, CW, AB, VY, YI, SS, IN, YX No competing interests declared
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