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Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19
Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation.(1) Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases,(2) while mitotic exit is achieved by counteracting dephosphorylation, a process driven by...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491220/ https://www.ncbi.nlm.nih.gov/pubmed/37693408 http://dx.doi.org/10.1101/2023.08.31.555365 |
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author | Padi, Sathish K.R. Vos, Margaret R. Godek, Rachel J. Fuller, James R. Kruse, Thomas Hein, Jamin B. Nilsson, Jakob Kelker, Matthew S. Page, Rebecca Peti, Wolfgang |
author_facet | Padi, Sathish K.R. Vos, Margaret R. Godek, Rachel J. Fuller, James R. Kruse, Thomas Hein, Jamin B. Nilsson, Jakob Kelker, Matthew S. Page, Rebecca Peti, Wolfgang |
author_sort | Padi, Sathish K.R. |
collection | PubMed |
description | Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation.(1) Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases,(2) while mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55.(3) While the role of kinases in mitotic entry is well-established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited.(4) For PP2A:B55, inhibition is achieved by the two intrinsically disordered proteins (IDPs), ARPP19 (phosphorylation-dependent)(6,7) and FAM122A(5) (inhibition is phosphorylation-independent). Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies both IDPs bind PP2A:B55, but do so in highly distinct manners, unexpectedly leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provides a molecular roadmap for the development of therapeutic interventions for PP2A:B55 related diseases. |
format | Online Article Text |
id | pubmed-10491220 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104912202023-09-09 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 Padi, Sathish K.R. Vos, Margaret R. Godek, Rachel J. Fuller, James R. Kruse, Thomas Hein, Jamin B. Nilsson, Jakob Kelker, Matthew S. Page, Rebecca Peti, Wolfgang bioRxiv Article Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation.(1) Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases,(2) while mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55.(3) While the role of kinases in mitotic entry is well-established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited.(4) For PP2A:B55, inhibition is achieved by the two intrinsically disordered proteins (IDPs), ARPP19 (phosphorylation-dependent)(6,7) and FAM122A(5) (inhibition is phosphorylation-independent). Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies both IDPs bind PP2A:B55, but do so in highly distinct manners, unexpectedly leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provides a molecular roadmap for the development of therapeutic interventions for PP2A:B55 related diseases. Cold Spring Harbor Laboratory 2023-08-31 /pmc/articles/PMC10491220/ /pubmed/37693408 http://dx.doi.org/10.1101/2023.08.31.555365 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Padi, Sathish K.R. Vos, Margaret R. Godek, Rachel J. Fuller, James R. Kruse, Thomas Hein, Jamin B. Nilsson, Jakob Kelker, Matthew S. Page, Rebecca Peti, Wolfgang Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title | Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title_full | Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title_fullStr | Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title_full_unstemmed | Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title_short | Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19 |
title_sort | cryo-em structures of pp2a:b55-fam122a and pp2a:b55-arpp19 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491220/ https://www.ncbi.nlm.nih.gov/pubmed/37693408 http://dx.doi.org/10.1101/2023.08.31.555365 |
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