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dc.contributor.authorMortuza, Gulnahar B
dc.contributor.authorHermida, Dario
dc.contributor.authorPedersen, Anna-Kathrine
dc.contributor.authorSegura-Bayona, Sandra
dc.contributor.authorLópez-Méndez, Blanca
dc.contributor.authorRedondo P, Pilar 
dc.contributor.authorRüther, Patrick
dc.contributor.authorPozdnyakova, Irina
dc.contributor.authorGarrote, Ana M
dc.contributor.authorMuñoz, Ines Gabriela 
dc.contributor.authorVillamor-Payà, Marina
dc.contributor.authorJauset, Cristina
dc.contributor.authorOlsen, Jesper V
dc.contributor.authorStracker, Travis H
dc.contributor.authorMontoya, Guillermo
dc.date.accessioned2018-10-25T09:02:52Z
dc.date.available2018-10-25T09:02:52Z
dc.date.issued2018-06-28
dc.identifier.citationNat Commun. 2018; 9(1): 2535.es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6526
dc.description.abstractTousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.es_ES
dc.description.sponsorshipNovo Nordisk Foundation Center for Protein Research is supported fi nancially by the Novo Nordisk Foundation (Grant NNF14CC0001) and the Danish Cancer Foundation for a grant to G.M. T.H.S. is supported by the Ministerio de Economía y Competitividad (MINECO) (BFU2015-68354, Ayudas para incentivar la incorporación estable de doc- tores (IED) 2015 and institutional funding through the Centres of Excellence Severo Ochoa award and from the CERCA Programme of the Catalan Government), S.S.B. by a predoctoral fellowship from Fundacio La Caixa and M.V.P. by a Severo Ochoa FPI predoctoral fellowship (MINECO). P.R. is supported by the Marie Sk ł odowska-Curie European Training Network (ETN) “ TEMPERA. We would like to thank the Protein Production Facility Platform at CPR for the excellent technical assistance, M. Orozco at IRB Barcelona for helping with the initial modelling analysis and also thank the PRO-MS Danish National Mass Spectrometry Platform for Functional Proteomics and the CPR Mass Spectrometry Platform for instrument support and assistance.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDNA-DAMAGE CHECKPOINTes_ES
dc.subjectPROTEIN-KINASEes_ES
dc.subjectS-PHASEes_ES
dc.subjectGENOMIC INSTABILITYes_ES
dc.subjectBREAST-CANCERes_ES
dc.subjectCELL-CYCLEes_ES
dc.subjectREPLICATIONes_ES
dc.subjectASF1es_ES
dc.subjectPHOSPHORYLATIONes_ES
dc.subjectIDENTIFICATIONes_ES
dc.titleMolecular basis of Tousled-Like Kinase 2 activationes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID29955062es_ES
dc.format.volume9es_ES
dc.format.number1es_ES
dc.format.page2535es_ES
dc.identifier.doi10.1038/s41467-018-04941-yes_ES
dc.contributor.funderNovo Nordisk Foundation 
dc.contributor.funderDanish Cancer Foundation
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderFundación La Caixa 
dc.identifier.e-issn2041-1723es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41467- 018-04941-yes_ES
dc.identifier.journalNature communicationses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigaciónes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicases_ES
dc.relation.projectIDMINECO/ICTI2013-2016/BFU2015-68354es_ES
dc.rights.accessRightsopen accesses_ES


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