SUMOylation of protein phosphatase 5 regulates phosphatase activity and substrate release.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-09-20 DOI:10.1038/s44319-024-00250-2

Rebecca A Sager, Sarah J Backe, Diana M Dunn, Jennifer A Heritz, Elham Ahanin, Natela Dushukyan, Barry Panaretou, Gennady Bratslavsky, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour

{"title":"SUMOylation of protein phosphatase 5 regulates phosphatase activity and substrate release.","authors":"Rebecca A Sager, Sarah J Backe, Diana M Dunn, Jennifer A Heritz, Elham Ahanin, Natela Dushukyan, Barry Panaretou, Gennady Bratslavsky, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour","doi":"10.1038/s44319-024-00250-2","DOIUrl":null,"url":null,"abstract":"<p><p>The serine/threonine protein phosphatase 5 (PP5) regulates hormone and stress-induced signaling networks. Unlike other phosphoprotein phosphatases, PP5 contains both regulatory and catalytic domains and is further regulated through post-translational modifications (PTMs). Here we identify that SUMOylation of K430 in the catalytic domain of PP5 regulates phosphatase activity. Additionally, phosphorylation of PP5-T362 is pre-requisite for SUMOylation, suggesting the ordered addition of PTMs regulates PP5 function in cells. Using the glucocorticoid receptor, a well known substrate for PP5, we demonstrate that SUMOylation results in substrate release from PP5. We harness this information to create a non-SUMOylatable K430R mutant as a 'substrate trap' and globally identified novel PP5 substrate candidates. Lastly, we generated a consensus dephosphorylation motif using known substrates, and verified its presence in the new candidate substrates. This study unravels the impact of cross talk of SUMOylation and phosphorylation on PP5 phosphatase activity and substrate release in cells.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4636-4654"},"PeriodicalIF":6.5000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549447/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44319-024-00250-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The serine/threonine protein phosphatase 5 (PP5) regulates hormone and stress-induced signaling networks. Unlike other phosphoprotein phosphatases, PP5 contains both regulatory and catalytic domains and is further regulated through post-translational modifications (PTMs). Here we identify that SUMOylation of K430 in the catalytic domain of PP5 regulates phosphatase activity. Additionally, phosphorylation of PP5-T362 is pre-requisite for SUMOylation, suggesting the ordered addition of PTMs regulates PP5 function in cells. Using the glucocorticoid receptor, a well known substrate for PP5, we demonstrate that SUMOylation results in substrate release from PP5. We harness this information to create a non-SUMOylatable K430R mutant as a 'substrate trap' and globally identified novel PP5 substrate candidates. Lastly, we generated a consensus dephosphorylation motif using known substrates, and verified its presence in the new candidate substrates. This study unravels the impact of cross talk of SUMOylation and phosphorylation on PP5 phosphatase activity and substrate release in cells.

查看原文本刊更多论文

蛋白磷酸酶 5 的 SUMO 化调节磷酸酶活性和底物释放。

丝氨酸/苏氨酸蛋白磷酸酶 5（PP5）调节激素和压力诱导的信号网络。与其他磷蛋白磷酸酶不同，PP5 同时含有调节结构域和催化结构域，并通过翻译后修饰（PTMs）进一步调控。在这里，我们发现 PP5 催化域 K430 的 SUMOylation 可调控磷酸酶的活性。此外，PP5-T362 的磷酸化是 SUMOylation 的先决条件，这表明 PTM 的有序添加调节 PP5 在细胞中的功能。糖皮质激素受体是 PP5 众所周知的底物，我们利用糖皮质激素受体证明了 SUMO 化会导致 PP5 释放底物。我们利用这一信息创建了一个不可SUMOylatable的K430R突变体作为 "底物陷阱"，并在全球范围内鉴定了新的PP5候选底物。最后，我们利用已知底物生成了共识去磷酸化基团，并在新的候选底物中验证了它的存在。这项研究揭示了 SUMOylation 和磷酸化交叉作用对细胞中 PP5 磷酸酶活性和底物释放的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.