Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
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
_version_ 1785104016270688256
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
work_keys_str_mv AT padisathishkr cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT vosmargaretr cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT godekrachelj cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT fullerjamesr cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT krusethomas cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT heinjaminb cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT nilssonjakob cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT kelkermatthews cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT pagerebecca cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19
AT petiwolfgang cryoemstructuresofpp2ab55fam122aandpp2ab55arpp19