Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

DC FieldValueLanguage
dc.contributor.authorWilmes, Stephan
dc.contributor.authorHafer, Maximillian
dc.contributor.authorVuorio, Joni
dc.contributor.authorTucker, Julie A.
dc.contributor.authorWinkelmann, Hauke
dc.contributor.authorLoechte, Sara
dc.contributor.authorStanly, Tess A.
dc.contributor.authorPrieto, Katiuska D. Pulgar
dc.contributor.authorPoojari, Chetan
dc.contributor.authorSharma, Vivek
dc.contributor.authorRichter, Christian P.
dc.contributor.authorKurre, Rainer
dc.contributor.authorHubbard, Stevan R.
dc.contributor.authorGarcia, K. Christopher
dc.contributor.authorMoraga, Ignacio
dc.contributor.authorVattulainen, Ilpo
dc.contributor.authorHitchcock, Ian S.
dc.contributor.authorPiehler, Jacob
dc.date.accessioned2021-12-23T16:23:23Z-
dc.date.available2021-12-23T16:23:23Z-
dc.date.issued2020
dc.identifier.issn00368075
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/14525-
dc.description.abstractHomodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.
dc.description.sponsorshipDeutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944 P8/Z, PI 405/14-1, PI 405/15-1]; long-term EMBO fellowshipEuropean Molecular Biology Organization (EMBO) [ALTF 454-2017]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-AI51321, 5R01AI101256]; Academy of Finland Center of Excellence programAcademy of Finland; Sigrid Juselius FoundationSigrid Juselius Foundation; European Research Council (CROWDED-PRO-LIPIDS); Helsinki Institute of Life Science (HiLIFE) Fellow project; Academy of FinlandAcademy of FinlandEuropean Commission; University of Helsinki; Ludwig and Mathers Foundations; HHMIHoward Hughes Medical Institute; CRUKCancer Research UK [A24593]; Horizon 2020 Framework program [714680]; Wellcome TrustWellcome TrustEuropean Commission; Royal Society Sir Henry Dale Fellowship [202323/Z/16/z]; Supported by Deutsche Forschungsgemeinschaft grants SFB 944 P8/Z, PI 405/14-1, and PI 405/15-1 (J.P. and R.K.); long-term EMBO fellowship ALTF 454-2017 (S.W.); NIH grant 5R01AI101256 (S.R.H.); the Academy of Finland Center of Excellence program, the Sigrid Juselius Foundation, the European Research Council (CROWDED-PRO-LIPIDS), and the Helsinki Institute of Life Science (HiLIFE) Fellow project (I.V.); the Academy of Finland, the Sigrid Juselius Foundation, and the University of Helsinki (V.S.); NIH grant R01-AI51321, the Ludwig and Mathers Foundations, and HHMI (K.C.G.); CRUK grant A24593 (I.S.H.); and Horizon 2020 Framework program grant 714680, the Wellcome Trust, and Royal Society Sir Henry Dale Fellowship 202323/Z/16/z (I.M.).
dc.language.isoen
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartofSCIENCE
dc.subjectCONSTITUTIVE ACTIVATION
dc.subjectDIMERIZATION
dc.subjectDYNAMICS
dc.subjectERYTHROPOIETIN RECEPTOR
dc.subjectGROWTH-HORMONE RECEPTOR
dc.subjectJAK2
dc.subjectLIGAND
dc.subjectMultidisciplinary Sciences
dc.subjectPSEUDOKINASE-DOMAIN
dc.subjectScience & Technology - Other Topics
dc.subjectSTRUCTURAL BASIS
dc.subjectTHROMBOPOIETIN RECEPTOR
dc.titleMechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
dc.typejournal article
dc.identifier.doi10.1126/science.aaw3242
dc.identifier.isiISI:000512382900025
dc.description.volume367
dc.description.issue6478
dc.description.startpage643+
dc.contributor.orcid0000-0002-6119-676X
dc.contributor.orcid0000-0003-2404-4545
dc.contributor.orcid0000-0001-6575-221X
dc.contributor.orcid0000-0002-4112-710X
dc.contributor.orcid0000-0001-7408-3214
dc.contributor.orcid0000-0003-3688-6854
dc.contributor.orcid0000-0002-2707-9383
dc.contributor.orcid0000-0001-9909-0701
dc.contributor.orcid0000-0002-8838-3151
dc.contributor.researcheridAAT-1513-2021
dc.identifier.eissn10959203
dc.publisher.place1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA
dcterms.isPartOf.abbreviationScience
dcterms.oaStatusGreen Accepted
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptidfb05-
crisitem.author.deptidfb05-
crisitem.author.orcid0000-0002-6872-6567-
crisitem.author.orcid0000-0002-2143-2270-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidKuRa617-
crisitem.author.netidPiJa938-
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