PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

Protein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine protein phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to th...

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Autores principales:	Holly Fowle, Ziran Zhao, Qifang Xu, Jason S Wasserman, Xinru Wang, Mary Adeyemi, Felicity Feiser, Alison N Kurimchak, Diba Atar, Brennan C McEwan, Arminja N Kettenbach, Rebecca Page, Wolfgang Peti, Roland L Dunbrack, Xavier Graña
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	serine-threonine phosphatase PP2A phosphorylation enzyme p107 TAU Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6761c6a9c42749159283c5b22082407f
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spelling	oai:doaj.org-article:6761c6a9c42749159283c5b22082407f2021-11-08T08:19:06ZPP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p10710.7554/eLife.631812050-084Xe63181https://doaj.org/article/6761c6a9c42749159283c5b22082407f2021-10-01T00:00:00Zhttps://elifesciences.org/articles/63181https://doaj.org/toc/2050-084XProtein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine protein phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55α recruits p107, a pRB-related tumor suppressor and B55α substrate. Using molecular and cellular approaches, we identified a conserved region 1 (R1, residues 615–626) encompassing the strongest p107 binding site. This enabled us to identify an ‘HxRVxxV619-625’ short linear motif (SLiM) in p107 as necessary for B55α binding and dephosphorylation of the proximal pSer-615 in vitro and in cells. Numerous B55α/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, ‘p[ST]-P-x(4,10)-[RK]-V-x-x-[VI]-R.’ Mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α, validating its generality. A data-guided computational model details the interaction of residues from the conserved p107 SLiM, the B55α groove, and phosphosite presentation. Altogether, these data provide key insights into PP2A/B55α’s mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55α’s role in multiple cellular processes.Holly FowleZiran ZhaoQifang XuJason S WassermanXinru WangMary AdeyemiFelicity FeiserAlison N KurimchakDiba AtarBrennan C McEwanArminja N KettenbachRebecca PageWolfgang PetiRoland L DunbrackXavier GrañaeLife Sciences Publications Ltdarticleserine-threonine phosphatasePP2Aphosphorylationenzymep107TAUMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	serine-threonine phosphatase PP2A phosphorylation enzyme p107 TAU Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	serine-threonine phosphatase PP2A phosphorylation enzyme p107 TAU Medicine R Science Q Biology (General) QH301-705.5 Holly Fowle Ziran Zhao Qifang Xu Jason S Wasserman Xinru Wang Mary Adeyemi Felicity Feiser Alison N Kurimchak Diba Atar Brennan C McEwan Arminja N Kettenbach Rebecca Page Wolfgang Peti Roland L Dunbrack Xavier Graña PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
description	Protein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine protein phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55α recruits p107, a pRB-related tumor suppressor and B55α substrate. Using molecular and cellular approaches, we identified a conserved region 1 (R1, residues 615–626) encompassing the strongest p107 binding site. This enabled us to identify an ‘HxRVxxV619-625’ short linear motif (SLiM) in p107 as necessary for B55α binding and dephosphorylation of the proximal pSer-615 in vitro and in cells. Numerous B55α/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, ‘p[ST]-P-x(4,10)-[RK]-V-x-x-[VI]-R.’ Mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α, validating its generality. A data-guided computational model details the interaction of residues from the conserved p107 SLiM, the B55α groove, and phosphosite presentation. Altogether, these data provide key insights into PP2A/B55α’s mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55α’s role in multiple cellular processes.
format	article
author	Holly Fowle Ziran Zhao Qifang Xu Jason S Wasserman Xinru Wang Mary Adeyemi Felicity Feiser Alison N Kurimchak Diba Atar Brennan C McEwan Arminja N Kettenbach Rebecca Page Wolfgang Peti Roland L Dunbrack Xavier Graña
author_facet	Holly Fowle Ziran Zhao Qifang Xu Jason S Wasserman Xinru Wang Mary Adeyemi Felicity Feiser Alison N Kurimchak Diba Atar Brennan C McEwan Arminja N Kettenbach Rebecca Page Wolfgang Peti Roland L Dunbrack Xavier Graña
author_sort	Holly Fowle
title	PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
title_short	PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
title_full	PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
title_fullStr	PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
title_full_unstemmed	PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
title_sort	pp2a/b55α substrate recruitment as defined by the retinoblastoma-related protein p107
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/6761c6a9c42749159283c5b22082407f
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PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

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