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dc.contributor.authorLe Coq, Johanne 
dc.contributor.authorCamacho-Artacho, Marta
dc.contributor.authorVelázquez, José Vicente
dc.contributor.authorSantiveri, Clara M
dc.contributor.authorGallego, Luis Heredia
dc.contributor.authorCampos Olivas, Ramon 
dc.contributor.authorDölker, Nicole
dc.contributor.authorLietha, Daniel
dc.date.accessioned2019-02-06T10:51:55Z
dc.date.available2019-02-06T10:51:55Z
dc.date.issued2017
dc.identifier.citationElife. 2017;6; pii: e26640.es_ES
dc.identifier.issn2050-084Xes_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7132
dc.description.abstractSH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain. Both the phosphatase and C2 domains bind phosphatidylserine lipids, which likely helps to position the active site towards its substrate. Although located distant to the active site, the C2 domain greatly enhances catalytic turnover. Employing molecular dynamics, mutagenesis and cell biology, we identify two distinct allosteric signaling pathways, emanating from hydrophobic or polar interdomain interactions, differentially affecting lipid chain or headgroup moieties of PI(3,4,5)P3. Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.es_ES
dc.description.sponsorshipWe thank Jose´ Terro´ n Bautista for help with MD analysis. We thank the ESRF and ALBA for provid- ing the synchrotron-radiation facilities and the staff for their assistance in the data collection. We are grateful to the Barcelona Supercomputing Centre and National Supercomputing Centre (BSC-CNS) for allocating computer time to run the reported simulations. The work was supported by the Span- ish Ministry of Economy, Industry and Competitiveness (MEIC) Grants BFU2010-15923 (DL) and MEIC Project Retos BFU2016-77665-R co-funded by the European Regional Development Fund (ERDF) (DL), the Comunidad Auto´ noma de Madrid Grant S2010/BMD-2457 (DL), and by the National Cancer Research Centre. DL is also a recipient of awards from the Volkswagen Foundation (Az: 86 416–1) and Worldwide Cancer Research (15-1177).es_ES
dc.language.isoenges_ES
dc.publishereLife Sciences Publications es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectC2 domaines_ES
dc.subjectE. colies_ES
dc.subjectInositol phosphatasees_ES
dc.subjectallosteric regulationes_ES
dc.subjectbiochemistryes_ES
dc.subjectbiophysicses_ES
dc.subjectenzyme kineticses_ES
dc.subjecthumanes_ES
dc.subjectphosphatidylinositol-3,4,5-trisphosphatees_ES
dc.subjectstructural biologyes_ES
dc.subject.meshCatalytic Domain es_ES
dc.subject.meshCrystallography, X-Ray es_ES
dc.subject.meshDNA Mutational Analysis es_ES
dc.subject.meshHumans es_ES
dc.subject.meshModels, Moleculares_ES
dc.subject.meshMolecular Dynamics Simulation es_ES
dc.subject.meshPhosphatidylinositol Phosphates es_ES
dc.subject.meshPhosphatidylinositol-3,4,5-Trisphosphate 5-Phosphataseses_ES
dc.subject.meshPhosphatidylserines es_ES
dc.subject.meshProtein Binding es_ES
dc.subject.meshProtein Conformation es_ES
dc.subject.meshProtein Domains es_ES
dc.titleStructural basis for interdomain communication in SHIP2 providing high phosphatase activityes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID28792888es_ES
dc.format.volume6es_ES
dc.identifier.doi10.7554/eLife.26640es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2050-084Xes_ES
dc.relation.publisherversionhttps://doi.org/10.7554/eLife.26640.es_ES
dc.identifier.journaleLifees_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Espectroscopía y RMNes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2010-15923es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2016-77665-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/S2010/BMD-2457es_ES
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
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