Mechanism of Homodimeric Cytokine Receptor Activation and Dysregulation by Oncogenic Mutations

Overview

Journal Science

Specialty Science

Date 2020 Feb 8

PMID 32029621

Citations 82

Authors

Stephan Wilmes

Maximillian Hafer

Joni Vuorio

Julie A Tucker

Hauke Winkelmann

Sara Lochte

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

Affiliations

Soon will be listed here.

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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