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Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

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Details

Original languageEnglish
Pages (from-to)643-652
Number of pages10
JournalScience
Volume367
Issue number6478
DOIs
Publication statusPublished - 7 Feb 2020
Publication typeA1 Journal article-refereed

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.

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Field of science, Statistics Finland