• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

耦合到短线性基序中，在 PP2A 全酶去甲基化和抑制中产生了多功能的 PME-1 活性。

Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition.

机构信息

McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, United States.

Biophysics program, University of Wisconsin at Madison, Madison, United States.

出版信息

Elife. 2022 Aug 4;11:e79736. doi: 10.7554/eLife.79736.

DOI:10.7554/eLife.79736
PMID:35924897
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9398451/
Abstract

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.

摘要

蛋白磷酸酶 2A（PP2A）全酶通过调节亚基识别短序列来靶向广泛的底物。PP2A 甲酯酶 1（PME-1）是一种促进癌症的酶，与 PP2A 核心酶结合后会发生甲酯酶激活。在这里，我们表明 PME-1 可以轻易地去甲基化不同家族的 PP2A 全酶，并在体外阻断底物识别。PP2A-B56 全酶-PME-1 复合物的高分辨率冷冻电子显微镜结构表明，PME-1 的无规则区域，包括一个底物模拟序列，通过远程位点与 B56 调节亚基连接。它们占据全酶的底物结合槽，并允许全酶和 PME-1 发生大的结构位移，从而在结构化核心中实现多部分接触，以激活甲酯酶。B56 界面突变选择性地阻止 PME-1 对 PP2A-B56 全酶的活性，并影响总细胞 PP2A 的一部分甲基化。B56 界面突变使我们能够揭示 B56 特异性 PME-1 在 p53 信号转导中的功能。我们的研究揭示了 PME-1 抑制全酶功能的多种机制，以及源自将底物模拟序列与动态结构化核心结合的多功能 PME-1 活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/6f9582b1a8eb/elife-79736-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/2933512a3cbb/elife-79736-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/69f21845ae3c/elife-79736-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/392be7c9d889/elife-79736-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/be3f8fdbe186/elife-79736-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/6c27d4b4cbec/elife-79736-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/f6ce2618a80d/elife-79736-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/59e2ebf170e8/elife-79736-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/65b8740b7a20/elife-79736-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/b09c30590271/elife-79736-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/8414f163f135/elife-79736-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/7d1593e1a5cd/elife-79736-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/4856a7385b10/elife-79736-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/7f97d3bca1d3/elife-79736-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/f0f62b82e053/elife-79736-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/fb7a2d795469/elife-79736-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/d1261adc4fd5/elife-79736-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/ab15d77ac969/elife-79736-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/6f9582b1a8eb/elife-79736-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/2933512a3cbb/elife-79736-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/69f21845ae3c/elife-79736-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/392be7c9d889/elife-79736-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/be3f8fdbe186/elife-79736-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/6c27d4b4cbec/elife-79736-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/f6ce2618a80d/elife-79736-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/59e2ebf170e8/elife-79736-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/65b8740b7a20/elife-79736-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/b09c30590271/elife-79736-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/8414f163f135/elife-79736-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/7d1593e1a5cd/elife-79736-fig3-figsupp4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/4856a7385b10/elife-79736-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/7f97d3bca1d3/elife-79736-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/f0f62b82e053/elife-79736-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/fb7a2d795469/elife-79736-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/d1261adc4fd5/elife-79736-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/ab15d77ac969/elife-79736-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c19/9398451/6f9582b1a8eb/elife-79736-fig7.jpg

相似文献

1
Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition.耦合到短线性基序中，在 PP2A 全酶去甲基化和抑制中产生了多功能的 PME-1 活性。
Elife. 2022 Aug 4;11:e79736. doi: 10.7554/eLife.79736.
2
Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function.B56 磷酸化和结合基序在 PP2A-B56 全酶生物学功能中的新兴作用。
Int J Mol Sci. 2024 Mar 10;25(6):3185. doi: 10.3390/ijms25063185.
3
Structural mechanism of demethylation and inactivation of protein phosphatase 2A.蛋白磷酸酶2A去甲基化与失活的结构机制
Cell. 2008 Apr 4;133(1):154-63. doi: 10.1016/j.cell.2008.02.041.
4
A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment.动态的荷质相互作用调节 PP2A:B56 底物募集。
Elife. 2020 Mar 20;9:e55966. doi: 10.7554/eLife.55966.
5
A stable association with PME-1 may be dispensable for PP2A demethylation - implications for the detection of PP2A methylation and immunoprecipitation.与PME-1的稳定结合对于PP2A去甲基化可能并非必需——对PP2A甲基化检测和免疫沉淀的启示。
FEBS Open Bio. 2018 Aug 1;8(9):1486-1496. doi: 10.1002/2211-5463.12485. eCollection 2018 Sep.
6
Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B).蛋白磷酸酶2A催化亚基C末端亮氨酸残基的甲基化对于催化活性和调节亚基（PR55/B）的结合并非必需。
Biochem Biophys Res Commun. 2007 Mar 23;354(4):1052-7. doi: 10.1016/j.bbrc.2007.01.085. Epub 2007 Jan 24.
7
A PP1-PP2A phosphatase relay controls mitotic progression.蛋白磷酸酶1-蛋白磷酸酶2A磷酸酶接力控制有丝分裂进程。
Nature. 2015 Jan 1;517(7532):94-98. doi: 10.1038/nature14019. Epub 2014 Dec 10.
8
Structure of the protein phosphatase 2A holoenzyme.蛋白磷酸酶2A全酶的结构
Cell. 2006 Dec 15;127(6):1239-51. doi: 10.1016/j.cell.2006.11.033.
9
Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization.PP2A B56-BubR1复合物的晶体结构及其对PP2A底物募集和定位的影响。
Protein Cell. 2016 Jul;7(7):516-26. doi: 10.1007/s13238-016-0283-4. Epub 2016 Jun 28.
10
Regulation and role of the PP2A-B56 holoenzyme family in cancer.PP2A-B56 全酶家族在癌症中的调控和作用。
Biochim Biophys Acta Rev Cancer. 2023 Sep;1878(5):188953. doi: 10.1016/j.bbcan.2023.188953. Epub 2023 Jul 10.

引用本文的文献

1
Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function.B56 磷酸化和结合基序在 PP2A-B56 全酶生物学功能中的新兴作用。
Int J Mol Sci. 2024 Mar 10;25(6):3185. doi: 10.3390/ijms25063185.
2
GlPRMT5 inhibits GlPP2C1 via symmetric dimethylation and regulates the biosynthesis of secondary metabolites in Ganoderma lucidum.GlPRMT5 通过对称二甲基化抑制 GlPP2C1，从而调节灵芝中次生代谢物的生物合成。
Commun Biol. 2024 Feb 28;7(1):241. doi: 10.1038/s42003-024-05942-y.
3
B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.

本文引用的文献

1
Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling.系统发现短线性基序解码钙调磷酸酶信号。
Mol Cell. 2020 Jul 16;79(2):342-358.e12. doi: 10.1016/j.molcel.2020.06.029. Epub 2020 Jul 8.
2
A Consensus Binding Motif for the PP4 Protein Phosphatase.PP4 蛋白磷酸酶的共识结合基序。
Mol Cell. 2019 Dec 19;76(6):953-964.e6. doi: 10.1016/j.molcel.2019.08.029. Epub 2019 Oct 1.
3
Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment.有丝分裂信号通过募集蛋白磷酸酶2A（PP2A）刺激CREB辅激活因子CRTC3。
B56δ 长无序臂形成动态的 PP2A 调节界面，与全局变构和乔丹综合征突变相耦合。
Proc Natl Acad Sci U S A. 2024 Jan 2;121(1):e2310727120. doi: 10.1073/pnas.2310727120. Epub 2023 Dec 27.
4
PME-1 sensitizes glioblastoma cells to oxidative stress-induced cell death by attenuating PP2A-B55α-mediated inactivation of MAPKAPK2-RIPK1 signaling.PME-1通过减弱PP2A-B55α介导的MAPKAPK2-RIPK1信号失活，使胶质母细胞瘤细胞对氧化应激诱导的细胞死亡敏感。
Cell Death Discov. 2023 Jul 27;9(1):265. doi: 10.1038/s41420-023-01572-1.
5
Substrate and phosphorylation site selection by phosphoprotein phosphatases.磷酸化蛋白磷酸酶的底物和磷酸化位点选择。
Trends Biochem Sci. 2023 Aug;48(8):713-725. doi: 10.1016/j.tibs.2023.04.004. Epub 2023 May 10.
6
Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme.与PP2A-B56δ全酶中的变构网络和疾病突变相关的扩展调节界面。
bioRxiv. 2023 Apr 5:2023.03.09.530109. doi: 10.1101/2023.03.09.530109.
7
PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers.PP2A 甲基转移酶 PME-1 抑制失巢凋亡，与 PTEN 缺陷型前列腺癌的治疗复发相关。
Mol Oncol. 2023 Jun;17(6):1007-1023. doi: 10.1002/1878-0261.13353. Epub 2023 Apr 18.
8
Lipolysis of bone marrow adipocytes fuels bone.骨髓脂肪细胞的脂解作用为骨骼提供能量。
Nat Rev Endocrinol. 2022 Sep;18(9):522. doi: 10.1038/s41574-022-00723-1.
iScience. 2019 Jan 25;11:134-145. doi: 10.1016/j.isci.2018.12.012. Epub 2018 Dec 19.
4
A stable association with PME-1 may be dispensable for PP2A demethylation - implications for the detection of PP2A methylation and immunoprecipitation.与PME-1的稳定结合对于PP2A去甲基化可能并非必需——对PP2A甲基化检测和免疫沉淀的启示。
FEBS Open Bio. 2018 Aug 1;8(9):1486-1496. doi: 10.1002/2211-5463.12485. eCollection 2018 Sep.
5
Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1-binding RVxF motif in PP1 regulatory proteins.极光 B 通过磷酸化 PP1 调节蛋白中的保守 PP1 结合 RVxF 基序来拮抗有丝分裂中的 PP1 功能。
Sci Signal. 2018 May 15;11(530):eaai8669. doi: 10.1126/scisignal.aai8669.
6
Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression.Eya3与PP2A相互作用，诱导c-Myc稳定并促进肿瘤进展。
Nat Commun. 2018 Mar 13;9(1):1047. doi: 10.1038/s41467-018-03327-4.
7
Methylation-regulated decommissioning of multimeric PP2A complexes.甲基化调控多聚体 PP2A 复合物的退役。
Nat Commun. 2017 Dec 22;8(1):2272. doi: 10.1038/s41467-017-02405-3.
8
PP2A-B' holoenzyme substrate recognition, regulation and role in cytokinesis.PP2A-B' 全酶在胞质分裂中的底物识别、调控及作用
Cell Discov. 2017 Aug 8;3:17027. doi: 10.1038/celldisc.2017.27. eCollection 2017.
9
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy.MotionCor2：用于改进冷冻电子显微镜的束流诱导运动的各向异性校正
Nat Methods. 2017 Apr;14(4):331-332. doi: 10.1038/nmeth.4193. Epub 2017 Feb 27.
10
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination.cryoSPARC：用于快速无监督低温电子显微镜结构测定的算法。
Nat Methods. 2017 Mar;14(3):290-296. doi: 10.1038/nmeth.4169. Epub 2017 Feb 6.