Journal article
Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
ELife, Vol.11, e79736
08/01/2022
DOI: 10.7554/eLife.79736
PMCID: PMC9398451
PMID: 35924897
Abstract
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.
Details
- Title: Subtitle
- Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
- Creators
- Yitong Li - University of Wisconsin–MadisonVijaya Kumar Balakrishnan - University of Wisconsin–MadisonMichael Rowse - Indiana University – Purdue University ColumbusCheng-Guo Wu - University of Wisconsin–MadisonAnastasia Phoebe Bravos - University of Wisconsin–MadisonVikash K Yadav - Uppsala UniversityYlva Ivarsson - Uppsala UniversityStefan Strack - University of IowaIrina V Novikova - Environmental Molecular Sciences LaboratoryYongna Xing - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- ELife, Vol.11, e79736
- Publisher
- eLife Sciences Publications Ltd
- DOI
- 10.7554/eLife.79736
- PMID
- 35924897
- PMCID
- PMC9398451
- ISSN
- 2050-084X
- Grant note
- DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: GM137090-01; DOI: 10.13039/100000048, name: American Cancer Society, award: RSG-10-153-01-DMC; name: Jordan's Guardian Angels Foundation and Jordan's Syndrome research consortium fund from the State of California, award: A19-3376-5007; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: GM096060-01
- Language
- English
- Date published
- 08/01/2022
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984288742602771
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