Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
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 demethyla...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/79736 |
| _version_ | 1828222361715867648 |
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| author | Yitong Li Vijaya Kumar Balakrishnan Michael Rowse Cheng-Guo Wu Anastasia Phoebe Bravos Vikash K Yadav Ylva Ivarsson Stefan Strack Irina V Novikova Yongna Xing |
| author_facet | Yitong Li Vijaya Kumar Balakrishnan Michael Rowse Cheng-Guo Wu Anastasia Phoebe Bravos Vikash K Yadav Ylva Ivarsson Stefan Strack Irina V Novikova Yongna Xing |
| author_sort | Yitong Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:54:07Z |
| format | Article |
| id | doaj.art-c37f531dac834f918655f6dade4f99cc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:54:07Z |
| publishDate | 2022-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c37f531dac834f918655f6dade4f99cc2022-12-22T03:24:18ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.79736Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibitionYitong Li0https://orcid.org/0000-0002-7866-8460Vijaya Kumar Balakrishnan1Michael Rowse2https://orcid.org/0000-0002-5572-5258Cheng-Guo Wu3Anastasia Phoebe Bravos4Vikash K Yadav5Ylva Ivarsson6Stefan Strack7Irina V Novikova8Yongna Xing9https://orcid.org/0000-0002-9834-528XMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United StatesMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United StatesMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United StatesMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United States; Biophysics program, University of Wisconsin at Madison, Madison, United StatesMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United StatesDepartment of Chemistry – BMC, Uppsala University, Uppsala, SwedenDepartment of Chemistry – BMC, Uppsala University, Uppsala, SwedenDepartment of Neuroscience and Pharmacology, University of Iowa, Iowa City, United StatesEnvironmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, United StatesMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United States; Biophysics program, University of Wisconsin at Madison, Madison, United StatesProtein 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.https://elifesciences.org/articles/79736protein phosphatase 2APME-1demethylationshort linear motifsP53 |
| spellingShingle | Yitong Li Vijaya Kumar Balakrishnan Michael Rowse Cheng-Guo Wu Anastasia Phoebe Bravos Vikash K Yadav Ylva Ivarsson Stefan Strack Irina V Novikova Yongna Xing Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition eLife protein phosphatase 2A PME-1 demethylation short linear motifs P53 |
| title | Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| title_full | Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| title_fullStr | Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| title_full_unstemmed | Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| title_short | Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| title_sort | coupling to short linear motifs creates versatile pme 1 activities in pp2a holoenzyme demethylation and inhibition |
| topic | protein phosphatase 2A PME-1 demethylation short linear motifs P53 |
| url | https://elifesciences.org/articles/79736 |
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