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

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dc.citation.articleNumbere2015618118
dc.citation.issueNumber10
dc.citation.journalTitlePNAS
dc.citation.volumeNumber118
dc.contributor.authorYang, David S.
dc.contributor.authorSaeedi, Arash
dc.contributor.authorDavtyan, Aram
dc.contributor.authorFathi, Mohsen
dc.contributor.authorSherman, Michael B.
dc.contributor.authorSafari, Mohammad S.
dc.contributor.authorKlindziuk, Alena
dc.contributor.authorBarton, Michelle C.
dc.contributor.authorVaradarajan, Navin
dc.contributor.authorKolomeisky, Anatoly B.
dc.contributor.authorVekilov, Peter G.
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2021-03-24T20:51:07Z
dc.date.available2021-03-24T20:51:07Z
dc.date.issued2021
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.
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.
dc.identifier.doihttps://doi.org/10.1073/pnas.2015618118
dc.identifier.urihttps://hdl.handle.net/1911/110195
dc.language.isoeng
dc.publisherNational Academy of Sciences
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.
dc.titleMesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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