PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
Abstract 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(5-10)-[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 mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55〈 role in multiple cellular processes.
Fowle Holly、Feiser Felicity、Peti Wolfgang、Wang Xinru、Kettenbach Arminja N.、Kurimchak Alison、Xu Qifang、Adeyemi Mary、Gra?a Xavier、Dunbrack Roland L. Jr.、Page Rebecca、Zhao Ziran
Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of MedicineFels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of MedicineDepartment of Chemistry and Biochemistry, University of ArizonaDepartment of Chemistry and Biochemistry, University of ArizonaDepartment of Biochemistry and Cell Biology, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center at DartmouthFels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of MedicineInstitute for Cancer Research, Fox Chase Cancer CenterFels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of MedicineFels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of MedicineInstitute for Cancer Research, Fox Chase Cancer CenterDepartment of Chemistry and Biochemistry, University of ArizonaFels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine
分子生物学生物化学基础医学
Fowle Holly,Feiser Felicity,Peti Wolfgang,Wang Xinru,Kettenbach Arminja N.,Kurimchak Alison,Xu Qifang,Adeyemi Mary,Gra?a Xavier,Dunbrack Roland L. Jr.,Page Rebecca,Zhao Ziran.PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2021.03.02.433577.点此复制
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