Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
Wilmes S., Hafer M., Vuorio J., Tucker JA., Winkelmann H., Löchte S., Stanly TA., Pulgar Prieto KD., Poojari C., Sharma V., Richter CP., Kurre R., Hubbard SR., Garcia KC., Moraga I., Vattulainen I., Hitchcock IS., Piehler J.
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.