FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

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• dc.contributor.author Qamar, Seema
• dc.contributor.author Tartaglia, Gian Gaetano
• dc.contributor.author St George-Hyslop, Peter
• dc.date.accessioned 2019-11-04T08:47:32Z
• dc.date.available 2019-11-04T08:47:32Z
• dc.date.issued 2018
• dc.description.abstract Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.
• dc.description.sponsorship This work was supported by the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (to P.S.H.), Wellcome Trust (to P.S.H., M.V., D.K., T.K., C.F.K., and G.S.K.S.), a European Research Council starting grant (RIBOMYLOME_309545) (to G.G.T.), a European Research Council grant (322817) (to C.E.H.), the Swiss National Foundation for Science (to F.S.R.), and the ALS Society of Canada/Brain Canada (to P.S.H.).
• dc.format.mimetype application/pdf
• dc.identifier.citation Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell. 2018;173(3):720-34. DOI: 10.1016/j.cell.2018.03.056
• dc.identifier.doi http://dx.doi.org/10.1016/j.cell.2018.03.056
• dc.identifier.issn 0092-8674
• dc.identifier.uri http://hdl.handle.net/10230/42585
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell. 2018;173(3):720-34
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/322817
• dc.rights © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword AFM-IR
• dc.subject.keyword Arginine methylation
• dc.subject.keyword Cation-π
• dc.subject.keyword Citrullination
• dc.subject.keyword Frontotemporal dementia
• dc.subject.keyword Membraneless organelle
• dc.subject.keyword Neuronal ribonucleoprotein granule
• dc.subject.keyword Phase separation
• dc.subject.keyword Phase-sensitive fluorescent dyes
• dc.subject.keyword Synaptic new protein synthesis
• dc.title FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion