Mesoscopic p53-rich clusters represent a new class of protein condensates.

IF 2.9 Q2 BIOPHYSICS
Biophysics reviews Pub Date : 2025-03-20 eCollection Date: 2025-03-01 DOI:10.1063/5.0243722
David S Yang, Alexander Tilson, Michael B Sherman, Navin Varadarajan, Peter G Vekilov
{"title":"Mesoscopic p53-rich clusters represent a new class of protein condensates.","authors":"David S Yang, Alexander Tilson, Michael B Sherman, Navin Varadarajan, Peter G Vekilov","doi":"10.1063/5.0243722","DOIUrl":null,"url":null,"abstract":"<p><p>The protein p53 is an important tumor suppressor, which transforms, after mutation, into a potent cancer promotor. Both mutant and wild-type p53 form amyloid fibrils, and fibrillization is considered one of the pathways of the mutants' oncogenicity. p53 incorporates structured domains, essential to its function, and extensive disordered regions. Here, we address the roles of the ordered (where the vast majority of oncogenic mutations localize) and disordered (implicated in aggregation and condensation of numerous other proteins) domains in p53 aggregation. We show that in the cytosol of model breast cancer cells, the mutant p53 R248Q reproducibly forms fluid aggregates with narrow size distribution centered at approximately 40 nm. Similar aggregates were observed in experiments with purified p53 R248Q, which identified the aggregates as mesoscopic protein-rich clusters, a unique protein condensate. Direct TEM imaging demonstrates that the mesoscopic clusters host and facilitate the nucleation of amyloid fibrils. We show that in solutions of stand-alone ordered domain of WT p53 clusters form and support fibril nucleation, whereas the disordered N-terminus domain forms common dense liquid and no fibrils. These results highlight two unique features of the mesoscopic protein-rich clusters: their role in amyloid fibrillization that may have implications for the oncogenicity of p53 mutants and the defining role of the ordered protein domains in their formation. In a broader context, these findings demonstrate that mutations in the DBD domain, which underlie the loss of cancer-protective transcription function, are also responsible for fibrillization and, thus, the gain of oncogenic function of p53 mutants.</p>","PeriodicalId":72405,"journal":{"name":"Biophysics reviews","volume":"6 1","pages":"011308"},"PeriodicalIF":2.9000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928095/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biophysics reviews","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1063/5.0243722","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 0

Abstract

The protein p53 is an important tumor suppressor, which transforms, after mutation, into a potent cancer promotor. Both mutant and wild-type p53 form amyloid fibrils, and fibrillization is considered one of the pathways of the mutants' oncogenicity. p53 incorporates structured domains, essential to its function, and extensive disordered regions. Here, we address the roles of the ordered (where the vast majority of oncogenic mutations localize) and disordered (implicated in aggregation and condensation of numerous other proteins) domains in p53 aggregation. We show that in the cytosol of model breast cancer cells, the mutant p53 R248Q reproducibly forms fluid aggregates with narrow size distribution centered at approximately 40 nm. Similar aggregates were observed in experiments with purified p53 R248Q, which identified the aggregates as mesoscopic protein-rich clusters, a unique protein condensate. Direct TEM imaging demonstrates that the mesoscopic clusters host and facilitate the nucleation of amyloid fibrils. We show that in solutions of stand-alone ordered domain of WT p53 clusters form and support fibril nucleation, whereas the disordered N-terminus domain forms common dense liquid and no fibrils. These results highlight two unique features of the mesoscopic protein-rich clusters: their role in amyloid fibrillization that may have implications for the oncogenicity of p53 mutants and the defining role of the ordered protein domains in their formation. In a broader context, these findings demonstrate that mutations in the DBD domain, which underlie the loss of cancer-protective transcription function, are also responsible for fibrillization and, thus, the gain of oncogenic function of p53 mutants.

介观富含p53的团簇代表了一类新的蛋白质凝聚体。
p53蛋白是一种重要的肿瘤抑制因子,它在突变后转化为一种强有力的癌症促进因子。突变型和野生型p53都能形成淀粉样蛋白原纤维,纤维化被认为是突变体致癌的途径之一。P53包含对其功能至关重要的结构化结构域和广泛的无序区域。在这里,我们讨论了有序结构域(绝大多数致癌突变定位的地方)和无序结构域(涉及许多其他蛋白质的聚集和冷凝)在p53聚集中的作用。我们发现,在模型乳腺癌细胞的细胞质中,突变体p53 R248Q可重复地形成以约40 nm为中心的狭窄尺寸分布的流体聚集体。在纯化的p53 R248Q实验中观察到类似的聚集体,这表明聚集体是一种独特的蛋白质凝析物,是一种富含介观蛋白质的聚集体。直接透射电镜成像显示,介观簇寄主并促进淀粉样蛋白原纤维成核。我们发现,在WT的独立有序结构域的溶液中,p53簇形成并支持纤维成核,而无序的n端结构域形成共同的致密液体,没有纤维。这些结果突出了介观富含蛋白质簇的两个独特特征:它们在淀粉样蛋白纤维化中的作用,可能对p53突变体的致癌性有影响,以及有序蛋白质结构域在其形成中的决定性作用。在更广泛的背景下,这些发现表明,DBD结构域的突变,是癌症保护转录功能丧失的基础,也是p53突变体成纤维化的原因,因此,p53突变体的致癌功能获得。
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
CiteScore
3.60
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信