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Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.

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dc.contributor.authorPal, Mohinder
dc.contributor.authorMuñoz-Hernandez, Hugo
dc.contributor.authorBjorklund, Dennis
dc.contributor.authorZhou, Lihong
dc.contributor.authorDegliesposti, Gianluca
dc.contributor.authorSkehel, J Mark
dc.contributor.authorHesketh, Emma L
dc.contributor.authorThompson, Rebecca F
dc.contributor.authorPearl, Laurence H
dc.contributor.authorLlorca Blanco, Oscar Antonio
dc.contributor.authorProdromou, Chrisostomos
dc.contributor.funderWellcome Trust
dc.contributor.funderUniversity of Leeds (Reino Unido)
dc.contributor.funderUK Research and Innovation
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)
dc.contributor.funderInstituto de Salud Carlos III
dc.date.accessioned2024-09-16T08:16:56Z
dc.date.available2024-09-16T08:16:56Z
dc.date.issued2021-07-06
dc.description.abstractThe R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, small nuclear ribonucleoprotein particles (snRNPs), and phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs) such as TOR and SMG1. PIKK stabilization depends on an additional complex of TELO2, TTI1, and TTI2 (TTT), whose structure and function are poorly understood. The cryoelectron microscopy (cryo-EM) structure of the human R2TP-TTT complex, together with biochemical experiments, reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Taken together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe are grateful to Pascale Schellenberger (University of Sussex) and Fabienne Beuron and Ed Morris (Institute of Cancer Research) for assistance with cryoEM grid preparation and evaluation and for useful discussion. We are grateful for access to the cryo-EM facility at the University of Sussex (funded by Wellcome Trust award enhancement grant 095605/Z/11/A [to L.H.P.] and the RM Phillips Trust) and FEI Krios Titan cryoelectron microscopes at the Astbury Biostructure Laboratory at the University of Leeds (funded by the University of Leeds ABSL award and Wellcome Trust award 108466/Z/15/Z) and at the UK National Electron Bio-imaging Centre (eBIC-Diamond, funded by the Wellcome Trust, MRC, and BBSRC). This work was supported by a Wellcome Trust senior investigator award (095605/Z/11/Z), a Wellcome Trust award enhancement grant (095605/Z/11/A) (to L.H.P.), a BBSRC project grant (BB/R01678X/1 to L.H.P. and C.P.), and by grants from the Spanish Ministry of Science and Innovation/Agencia Estatal de Investigacio n (MCI/AEI) co-funded by the European Regional Development Fund (ERDF) (SAF2017-82632-P), the Autonomous Region of Madrid co-funded by the European Social Fund and the European Regional Development Fund (Y2018/BIO4747 and P2018/NMT4443), and the support of the National Institute of Health Carlos III to CNIO (to O.L.).es_ES
dc.format.number1es_ES
dc.format.page109317es_ES
dc.format.volume36es_ES
dc.identifier.citationCell Rep . 2021 ;36(1):109317.es_ES
dc.identifier.doi10.1016/j.celrep.2021.109317es_ES
dc.identifier.e-issn2211-1247es_ES
dc.identifier.journalCell reportses_ES
dc.identifier.pubmedID34233195es_ES
dc.identifier.urihttps://hdl.handle.net/20.500.12105/23082
dc.language.isoenges_ES
dc.publisherCell Press
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/SAF2017-82632-Pes_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.celrep.2021.109317es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Complejos Macromoleculares en la Respuesta a Daños en el DNAes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subject.meshAdenosine Triphosphataseses_ES
dc.subject.meshCryoelectron Microscopyes_ES
dc.subject.meshHumanses_ES
dc.subject.meshModels, Moleculares_ES
dc.subject.meshMolecular Chaperoneses_ES
dc.subject.meshMultiprotein Complexeses_ES
dc.subject.meshProtein Bindinges_ES
dc.subject.meshProtein Domainses_ES
dc.subject.meshProtein Interaction Mappinges_ES
dc.subject.meshSaccharomyces cerevisiaees_ES
dc.subject.meshSaccharomyces cerevisiae Proteinses_ES
dc.subject.meshStructure-Activity Relationshipes_ES
dc.titleStructure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.es_ES
dc.typeresearch articlees_ES
dc.type.hasVersionVoRes_ES
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