Condensate formation of the human RNA-binding protein SMAUG1 is controlled by its intrinsically disordered regions and interactions with 14-3-3 proteins

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dc.contributor.authorCarey, Oliviaen
dc.contributor.authorFehilly, Johnen
dc.contributor.authorO'Leary, Eoghan Thomasen
dc.contributor.authorO'Shea, Stephenen
dc.contributor.authorJuda, Klaudiaen
dc.contributor.authorFitzel, Rahelen
dc.contributor.authorSelvaraj, Poojaen
dc.contributor.authorBurk, Katjaen
dc.contributor.authorLindsay, Andrew J.en
dc.contributor.authorYoung, Paulen
dc.contributor.authorPancsa, Ritaen
dc.contributor.authorMészáros, Bálinten
dc.contributor.authorDean, Kellieen
dc.contributor.funderAmerican Lebanese Syrian Associated Charitiesen
dc.contributor.funderTempus Közalapítványen
dc.contributor.funderIrish Research Councilen
dc.contributor.funderKøbenhavns Professionshøjskoleen
dc.contributor.funderMagyar Tudományos Akadémiaen
dc.contributor.funderNemzeti Kutatási Fejlesztési és Innovációs Hivatalen
dc.date.accessioned2025-07-17T14:43:56Z
dc.date.available2025-07-17T14:43:56Z
dc.date.issued2025-07-11en
dc.description.abstractSMAUG1 is a human RNA-binding protein (RBP) that is dysregulated in a wide range of diseases. It is evolutionarily conserved and forms condensates containing translationally repressed RNAs. This indicates that condensation is central to SMAUG1 function. In this work, we show that a prion-like disordered region within the C-terminal half of SMAUG1 is required, but not sufficient, to drive formation of liquid-like condensates in cells. We use biochemical assays to show that SMAUG1 liquid–liquid phase separation (LLPS) appears to be independent of RNA binding and does not depend on other large, disordered regions of the protein that potentially harbor several binding sites for partner proteins. Using a combination of computational predictions, structural modeling, in vitro and in cell measurements, we show that SMAUG1-driven condensation is negatively regulated by direct interactions with members of the 14-3-3 protein family. These interactions are mediated by at least four distinct phospho-regulated short linear motifs within the disordered regions of SMAUG1, working synergistically. Interactions between SMAUG1 and dimeric 14-3-3 proteins drive the dissolution of condensates and are likely intertwined with other unknown regulatory mechanisms. Interestingly, a monomeric 14-3-3 variant cannot induce condensate dissolution, suggesting that the conformational constraints imposed on the SMAUG1 polypeptide chain by dimeric 14-3-3 proteins, potentially bridging distant binding sites, are important for the described phase separation-regulatory mechanism. Our results reinforce recent findings on the general regulatory role of 14-3-3 proteins in biological condensation and provide valuable novel insights into how SMAUG1 phase separation is regulated.en
dc.description.sponsorshipIrish Research Council (GOIPG/2023/4569); Københavns Professionshøjskole (FK142285); Magyar Tudományos Akadémia (184018); Nemzeti Kutatási Fejlesztési és Innovációs Hivatal (BO/00174/22)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid169314en
dc.identifier.citationCarey, O., Fehilly, J., O'Leary, E. T., O’Shea, S., Juda, K., Fitzel, R., Selvaraj, P., Burk, K., Lindsay, A. J., Young, P. and Pancsa, R. (2025) 'Condensate formation of the human RNA-binding protein SMAUG1 is controlled by its intrinsically disordered regions and interactions with 14-3-3 proteins', Journal of Molecular Biology, 437(19), 169314 (28pp). https://doi.org/10.1016/j.jmb.2025.169314en
dc.identifier.doi10.1016/j.jmb.2025.169314en
dc.identifier.issn222836en
dc.identifier.issued19
dc.identifier.journaltitleJournal of Molecular Biologyen
dc.identifier.urihttps://hdl.handle.net/10468/17720
dc.identifier.volume437
dc.language.isoenen
dc.publisherAcademic Pressen
dc.rights© 2025, the Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject14-3-3en
dc.subjectBiomolecular condensationen
dc.subjectLiquid–liquid phase separationen
dc.subjectShort linear motifsen
dc.subjectSMAUG1en
dc.titleCondensate formation of the human RNA-binding protein SMAUG1 is controlled by its intrinsically disordered regions and interactions with 14-3-3 proteinsen
dc.typeArticle (peer reviewed)en
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