Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

Stephan Wilmes, Maximillian Hafer, Joni Vuorio, Julie A. Tucker, Hauke Winkelmann, Sara Löchte, Tess A. Stanly, Katiuska D. Pulgar Prieto, Chetan Poojari, Vivek Sharma, Christian P. Richter, Rainer Kurre, Stevan R. Hubbard, K. Christopher Garcia, Ignacio Moraga, Ilpo Vattulainen, Ian S. Hitchcock, Jacob Piehler (Lead / Corresponding author)

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2 Citations (Scopus)

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.

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

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Wilmes, S., Hafer, M., Vuorio, J., Tucker, J. A., Winkelmann, H., Löchte, S., Stanly, T. A., Pulgar Prieto, K. D., Poojari, C., Sharma, V., Richter, C. P., Kurre, R., Hubbard, S. R., Garcia, K. C., Moraga, I., Vattulainen, I., Hitchcock, I. S., & Piehler, J. (2020). Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science, 367(6478), 643-652. https://doi.org/10.1126/science.aaw3242