期刊
SCIENCE
卷 367, 期 6478, 页码 643-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaw3242
关键词
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资金
- Deutsche Forschungsgemeinschaft [SFB 944 P8/Z, PI 405/14-1, PI 405/15-1]
- long-term EMBO fellowship [ALTF 454-2017]
- NIH [R01-AI51321, 5R01AI101256]
- Academy of Finland Center of Excellence program
- Sigrid Juselius Foundation
- European Research Council (CROWDED-PRO-LIPIDS)
- Helsinki Institute of Life Science (HiLIFE) Fellow project
- Academy of Finland
- University of Helsinki
- Ludwig and Mathers Foundations
- HHMI
- CRUK [A24593]
- Horizon 2020 Framework program [714680]
- Wellcome Trust
- Royal Society Sir Henry Dale Fellowship [202323/Z/16/z]
- Wellcome Trust [202323/Z/16/Z] Funding Source: Wellcome Trust
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.
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