Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
DC Element | Wert | Sprache |
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dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Hafer, Maximillian | |
dc.contributor.author | Vuorio, Joni | |
dc.contributor.author | Tucker, Julie A. | |
dc.contributor.author | Winkelmann, Hauke | |
dc.contributor.author | Loechte, Sara | |
dc.contributor.author | Stanly, Tess A. | |
dc.contributor.author | Prieto, Katiuska D. Pulgar | |
dc.contributor.author | Poojari, Chetan | |
dc.contributor.author | Sharma, Vivek | |
dc.contributor.author | Richter, Christian P. | |
dc.contributor.author | Kurre, Rainer | |
dc.contributor.author | Hubbard, Stevan R. | |
dc.contributor.author | Garcia, K. Christopher | |
dc.contributor.author | Moraga, Ignacio | |
dc.contributor.author | Vattulainen, Ilpo | |
dc.contributor.author | Hitchcock, Ian S. | |
dc.contributor.author | Piehler, Jacob | |
dc.date.accessioned | 2021-12-23T16:23:23Z | - |
dc.date.available | 2021-12-23T16:23:23Z | - |
dc.date.issued | 2020 | |
dc.identifier.issn | 00368075 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14525 | - |
dc.description.abstract | Homodimeric 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.sponsorship | Deutsche 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.iso | en | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.relation.ispartof | SCIENCE | |
dc.subject | CONSTITUTIVE ACTIVATION | |
dc.subject | DIMERIZATION | |
dc.subject | DYNAMICS | |
dc.subject | ERYTHROPOIETIN RECEPTOR | |
dc.subject | GROWTH-HORMONE RECEPTOR | |
dc.subject | JAK2 | |
dc.subject | LIGAND | |
dc.subject | Multidisciplinary Sciences | |
dc.subject | PSEUDOKINASE-DOMAIN | |
dc.subject | Science & Technology - Other Topics | |
dc.subject | STRUCTURAL BASIS | |
dc.subject | THROMBOPOIETIN RECEPTOR | |
dc.title | Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations | |
dc.type | journal article | |
dc.identifier.doi | 10.1126/science.aaw3242 | |
dc.identifier.isi | ISI:000512382900025 | |
dc.description.volume | 367 | |
dc.description.issue | 6478 | |
dc.description.startpage | 643+ | |
dc.contributor.orcid | 0000-0002-6119-676X | |
dc.contributor.orcid | 0000-0003-2404-4545 | |
dc.contributor.orcid | 0000-0001-6575-221X | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0001-7408-3214 | |
dc.contributor.orcid | 0000-0003-3688-6854 | |
dc.contributor.orcid | 0000-0002-2707-9383 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0002-8838-3151 | |
dc.contributor.researcherid | AAT-1513-2021 | |
dc.identifier.eissn | 10959203 | |
dc.publisher.place | 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA | |
dcterms.isPartOf.abbreviation | Science | |
dcterms.oaStatus | Green Accepted | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-6872-6567 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | KuRa617 | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 15.05.2024