Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils

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dc.citation.articleNumbere2015618118en_US
dc.citation.issueNumber10en_US
dc.citation.journalTitlePNASen_US
dc.citation.volumeNumber118en_US
dc.contributor.authorYang, David S.en_US
dc.contributor.authorSaeedi, Arashen_US
dc.contributor.authorDavtyan, Aramen_US
dc.contributor.authorFathi, Mohsenen_US
dc.contributor.authorSherman, Michael B.en_US
dc.contributor.authorSafari, Mohammad S.en_US
dc.contributor.authorKlindziuk, Alenaen_US
dc.contributor.authorBarton, Michelle C.en_US
dc.contributor.authorVaradarajan, Navinen_US
dc.contributor.authorKolomeisky, Anatoly B.en_US
dc.contributor.authorVekilov, Peter G.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2021-03-24T20:51:07Zen_US
dc.date.available2021-03-24T20:51:07Zen_US
dc.date.issued2021en_US
dc.description.abstractThe protein p53 is a crucial tumor suppressor, often called “the guardian of the genome”; however, mutations transform p53 into a powerful cancer promoter. The oncogenic capacity of mutant p53 has been ascribed to enhanced propensity to fibrillize and recruit other cancer fighting proteins in the fibrils, yet the pathways of fibril nucleation and growth remain obscure. Here, we combine immunofluorescence three-dimensional confocal microscopy of human breast cancer cells with light scattering and transmission electron microscopy of solutions of the purified protein and molecular simulations to illuminate the mechanisms of phase transformations across multiple length scales, from cellular to molecular. We report that the p53 mutant R248Q (R, arginine; Q, glutamine) forms, both in cancer cells and in solutions, a condensate with unique properties, mesoscopic protein-rich clusters. The clusters dramatically diverge from other protein condensates. The cluster sizes are decoupled from the total cluster population volume and independent of the p53 concentration and the solution concentration at equilibrium with the clusters varies. We demonstrate that the clusters carry out a crucial biological function: they host and facilitate the nucleation of amyloid fibrils. We demonstrate that the p53 clusters are driven by structural destabilization of the core domain and not by interactions of its extensive unstructured region, in contradistinction to the dense liquids typical of disordered and partially disordered proteins. Two-step nucleation of mutant p53 amyloids suggests means to control fibrillization and the associated pathologies through modifying the cluster characteristics. Our findings exemplify interactions between distinct protein phases that activate complex physicochemical mechanisms operating in biological systems.en_US
dc.identifier.citationYang, David S., Saeedi, Arash, Davtyan, Aram, et al.. "Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils." <i>PNAS,</i> 118, no. 10 (2021) National Academy of Sciences: https://doi.org/10.1073/pnas.2015618118.en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2015618118en_US
dc.identifier.urihttps://hdl.handle.net/1911/110195en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the National Academy of Sciences.en_US
dc.titleMesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrilsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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