PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions
Abstract Protein Ser/Thr phosphatase PP1 is always associated with one or two regulatory subunits or RIPPOs. One of the earliest evolved RIPPOs is PPP1R2, also known as Inhibitor-2. Since its discovery nearly 5 decades ago, PPP1R2 has been variously described as an inhibitor, activator or (metal) ch...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54256-4 |
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| author | Sarah Lemaire Mónica Ferreira Zander Claes Rita Derua Madryn Lake Gerd Van der Hoeven Fabienne Withof Xinyu Cao Elora C. Greiner Arminja N. Kettenbach Aleyde Van Eynde Mathieu Bollen |
| author_facet | Sarah Lemaire Mónica Ferreira Zander Claes Rita Derua Madryn Lake Gerd Van der Hoeven Fabienne Withof Xinyu Cao Elora C. Greiner Arminja N. Kettenbach Aleyde Van Eynde Mathieu Bollen |
| author_sort | Sarah Lemaire |
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| description | Abstract Protein Ser/Thr phosphatase PP1 is always associated with one or two regulatory subunits or RIPPOs. One of the earliest evolved RIPPOs is PPP1R2, also known as Inhibitor-2. Since its discovery nearly 5 decades ago, PPP1R2 has been variously described as an inhibitor, activator or (metal) chaperone of PP1, but it is still unknown how PPP1R2 affects the function of PP1 in intact cells. Here, using specific research tools, we demonstrate that PPP1R2 stabilises a subgroup of PP1 holoenzymes, exemplified by PP1:RepoMan, thereby promoting the dephosphorylation of their substrates. Mechanistically, the recruitment of PPP1R2 disrupts an inhibitory, fuzzy interaction between the C-terminal tail and catalytic domain of PP1, and generates an additional C-terminal RepoMan-interaction site. The resulting holoenzyme is further stabilized by a direct PPP1R2:RepoMan interaction, which renders it refractory to competitive disruption by RIPPOs that do not interact with PPP1R2. Our data demonstrate that PPP1R2 modulates the function of PP1 by altering the balance between holoenzymes through stabilisation of specific subunit interactions. |
| format | Article |
| id | doaj-art-2fbdf03a68e8414dabd3add1e06c5217 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-2fbdf03a68e8414dabd3add1e06c52172024-11-17T12:37:34ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54256-4PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactionsSarah Lemaire0Mónica Ferreira1Zander Claes2Rita Derua3Madryn Lake4Gerd Van der Hoeven5Fabienne Withof6Xinyu Cao7Elora C. Greiner8Arminja N. Kettenbach9Aleyde Van Eynde10Mathieu Bollen11Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Protein Phosphorylation & Proteomics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenDepartment of Biochemistry and Cell Biology, Geisel School of Medicine at DartmouthDepartment of Biochemistry and Cell Biology, Geisel School of Medicine at DartmouthLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenLaboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of LeuvenAbstract Protein Ser/Thr phosphatase PP1 is always associated with one or two regulatory subunits or RIPPOs. One of the earliest evolved RIPPOs is PPP1R2, also known as Inhibitor-2. Since its discovery nearly 5 decades ago, PPP1R2 has been variously described as an inhibitor, activator or (metal) chaperone of PP1, but it is still unknown how PPP1R2 affects the function of PP1 in intact cells. Here, using specific research tools, we demonstrate that PPP1R2 stabilises a subgroup of PP1 holoenzymes, exemplified by PP1:RepoMan, thereby promoting the dephosphorylation of their substrates. Mechanistically, the recruitment of PPP1R2 disrupts an inhibitory, fuzzy interaction between the C-terminal tail and catalytic domain of PP1, and generates an additional C-terminal RepoMan-interaction site. The resulting holoenzyme is further stabilized by a direct PPP1R2:RepoMan interaction, which renders it refractory to competitive disruption by RIPPOs that do not interact with PPP1R2. Our data demonstrate that PPP1R2 modulates the function of PP1 by altering the balance between holoenzymes through stabilisation of specific subunit interactions.https://doi.org/10.1038/s41467-024-54256-4 |
| spellingShingle | Sarah Lemaire Mónica Ferreira Zander Claes Rita Derua Madryn Lake Gerd Van der Hoeven Fabienne Withof Xinyu Cao Elora C. Greiner Arminja N. Kettenbach Aleyde Van Eynde Mathieu Bollen PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions Nature Communications |
| title | PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions |
| title_full | PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions |
| title_fullStr | PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions |
| title_full_unstemmed | PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions |
| title_short | PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions |
| title_sort | ppp1r2 stimulates protein phosphatase 1 through stabilisation of dynamic subunit interactions |
| url | https://doi.org/10.1038/s41467-024-54256-4 |
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