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Aging can transform single-component protein condensates into multiphase architectures.

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cam.depositDate2022-06-28
cam.issuedOnline2022-06-21
cam.orpheus.success2022-07-01 - Embargo set during processing via Fast-track
dc.contributor.authorGaraizar, Adiran
dc.contributor.authorEspinosa, Jorge R
dc.contributor.authorJoseph, Jerelle A
dc.contributor.authorKrainer, Georg
dc.contributor.authorShen, Yi
dc.contributor.authorKnowles, Tuomas PJ
dc.contributor.authorCollepardo-Guevara, Rosana
dc.contributor.orcidGaraizar, Adiran [0000-0002-9320-2984]
dc.contributor.orcidEspinosa, Jorge R [0000-0001-9530-2658]
dc.contributor.orcidJoseph, Jerelle A [0000-0003-4525-180X]
dc.contributor.orcidKrainer, Georg [0000-0002-9626-7636]
dc.contributor.orcidShen, Yi [0000-0002-0456-3850]
dc.contributor.orcidCollepardo-Guevara, Rosana [0000-0003-1781-7351]
dc.date.accessioned2022-07-01T23:30:33Z
dc.date.available2022-07-01T23:30:33Z
dc.date.issued2022-06-28
dc.date.updated2022-06-28T15:38:23Z
dc.description.abstractPhase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multicomponent mixtures of biomolecules (e.g., proteins and nucleic acids) when the different components present sufficient physicochemical diversity (e.g., in intermolecular forces, structure, and chemical composition) to sustain separate coexisting phases. Because such diversity is highly coupled to the solution conditions (e.g., temperature, pH, salt, composition), it can manifest itself immediately from the nucleation and growth stages of condensate formation, develop spontaneously due to external stimuli or emerge progressively as the condensates age. Here, we investigate thermodynamic factors that can explain the progressive intrinsic transformation of single-component condensates into multiphase architectures during the nonequilibrium process of aging. We develop a multiscale model that integrates atomistic simulations of proteins, sequence-dependent coarse-grained simulations of condensates, and a minimal model of dynamically aging condensates with nonconservative intermolecular forces. Our nonequilibrium simulations of condensate aging predict that single-component condensates that are initially homogeneous and liquid like can transform into gel-core/liquid-shell or liquid-core/gel-shell multiphase condensates as they age due to gradual and irreversible enhancement of interprotein interactions. The type of multiphase architecture is determined by the aging mechanism, the molecular organization of the gel and liquid phases, and the chemical makeup of the protein. Notably, we predict that interprotein disorder to order transitions within the prion-like domains of intracellular proteins can lead to the required nonconservative enhancement of intermolecular interactions. Our study, therefore, predicts a potential mechanism by which the nonequilibrium process of aging results in single-component multiphase condensates.
dc.description.sponsorshipAdiran Garaizar acknowledges funding from the EPRSC (EP/N509620)
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.86090
dc.identifier.eissn1091-6490
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338677
dc.language.isoeng
dc.publisherProceedings of the National Academy of Sciences
dc.publisher.departmentDepartment of Chemistry
dc.publisher.urlhttp://dx.doi.org/10.1073/pnas.2119800119
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectbiomolecular condensates
dc.subjecthollow condensates
dc.subjectliquid–liquid phase separation
dc.subjectmultiscale modeling multiphase condensates
dc.subjectAging
dc.subjectBiomolecular Condensates
dc.subjectModels, Biological
dc.subjectMolecular Dynamics Simulation
dc.subjectProtein Conformation, beta-Strand
dc.subjectRNA-Binding Protein FUS
dc.subjectThermodynamics
dc.titleAging can transform single-component protein condensates into multiphase architectures.
dc.typeArticle
dcterms.dateAccepted2022-03-28
prism.issueIdentifier26
prism.publicationDate2022
prism.publicationNameProc Natl Acad Sci U S A
prism.startingPagee2119800119
prism.volume119
pubs.funder-project-idEuropean Research Council (803326)
pubs.funder-project-idEuropean Research Council (337969)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/P020259/1)
pubs.funder-project-idWellcome Trust (203249/Z/16/Z)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Future and Emerging Technologies (FET) (766972)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (841466)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1073/pnas.2119800119

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