Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
In: Science, Jg. 367 (2020-02-07), Heft 6478, S. 643-652
Online
academicJournal
Zugriff:
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. [ABSTRACT FROM AUTHOR]
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Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
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Autor/in / Beteiligte Person: | Wilmes, Stephan ; Hafer, Maximillian ; Vuorio, Joni ; Tucker, Julie A. ; Winkelmann, Hauke ; Löchte, Sara ; Stanly, Tess A. ; Prieto, Katiuska D. Pulgar ; Poojari, Chetan ; Sharma, Vivek ; Richter, Christian P. ; Kurre, Rainer ; Hubbard, Stevan R. ; Garcia, K. Christopher ; Moraga, Ignacio ; Vattulainen, Ilpo ; Hitchcock, Ian S. ; Piehler, Jacob |
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Zeitschrift: | Science, Jg. 367 (2020-02-07), Heft 6478, S. 643-652 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0036-8075 (print) |
DOI: | 10.1126/science.aaw3242 |
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