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dc.contributor.authorQamar, Seema
dc.contributor.authorWang, GuoZhen
dc.contributor.authorRandle, Suzanne J
dc.contributor.authorRuggeri, Francesco Simone
dc.contributor.authorVarela, Juan A
dc.contributor.authorLin, Julie Qiaojin
dc.contributor.authorPhillips, Emma C
dc.contributor.authorMiyashita, Akinori
dc.contributor.authorWilliams, Declan
dc.contributor.authorStröhl, Florian
dc.contributor.authorMeadows, William
dc.contributor.authorFerry, Rodylyn
dc.contributor.authorDardov, Victoria J
dc.contributor.authorTartaglia, Gian G
dc.contributor.authorFarrer, Lindsay A
dc.contributor.authorKaminski Schierle, Gabriele S
dc.contributor.authorKaminski, Clemens F
dc.contributor.authorHolt, Christine E
dc.contributor.authorFraser, Paul E
dc.contributor.authorSchmitt-Ulms, Gerold
dc.contributor.authorKlenerman, David
dc.contributor.authorKnowles, Tuomas
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorSt George-Hyslop, Peter
dc.date.accessioned2018-12-11T13:35:22Z
dc.date.available2018-12-11T13:35:22Z
dc.date.issued2018-04-19
dc.identifier256889174
dc.identifierec2c6209-50a9-40f5-ab68-d327ca765fb9
dc.identifier29677515
dc.identifier85045318029
dc.identifier.citationQamar , S , Wang , G , Randle , S J , Ruggeri , F S , Varela , J A , Lin , J Q , Phillips , E C , Miyashita , A , Williams , D , Ströhl , F , Meadows , W , Ferry , R , Dardov , V J , Tartaglia , G G , Farrer , L A , Kaminski Schierle , G S , Kaminski , C F , Holt , C E , Fraser , P E , Schmitt-Ulms , G , Klenerman , D , Knowles , T , Vendruscolo , M & St George-Hyslop , P 2018 , ' FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions ' , Cell , vol. 173 , no. 3 , e15 , pp. 720-734 . https://doi.org/10.1016/j.cell.2018.03.056en
dc.identifier.issn0092-8674
dc.identifier.otherPubMedCentral: PMC5927716
dc.identifier.otherORCID: /0000-0003-1901-1378/work/51700165
dc.identifier.urihttps://hdl.handle.net/10023/16663
dc.descriptionThis 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.).en
dc.description.abstractReversible 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.format.extent5903996
dc.language.isoeng
dc.relation.ispartofCellen
dc.subjectPhase separationen
dc.subjectNeuronal ribonucleoprotein granuleen
dc.subjectSynaptic new protein synthesisen
dc.subjectMembraneless organelleen
dc.subjectCation-πen
dc.subjectarginine methylationen
dc.subjectCitrullinationen
dc.subjectFrontotemporal dementiaen
dc.subjectAFM-IRen
dc.subjectPhase-sensitive fluorescent dyesen
dc.subjectQD Chemistryen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.subjectDASen
dc.subjectBDCen
dc.subjectR2Cen
dc.subject~DC~en
dc.subject.lccQDen
dc.subject.lccRC0321en
dc.titleFUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactionsen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.identifier.doihttps://doi.org/10.1016/j.cell.2018.03.056
dc.description.statusPeer revieweden


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