Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

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.

Source: ScienceNOW - February 5, 2020 Category: Science Authors: 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., Pi Tags: Biochemistry r-articles Source Type: news