Activated by interaction
Cytokines trigger immune responses when they bind to their cognate receptors. Class I cytokine receptors rely on the associated Janus kinase 2 (JAK2) to initiate signal transduction. There has been debate over whether activation involves ligand-induced dimerization of these receptors or ligand-induced conformational change of preformed dimers. Wilmes et al. imaged cytokine receptors in the plasma membranes of live human cells by single-molecule fluorescence microscopy and observed ligand-induced dimerization. They found that the JAK2 pseudokinase domains contribute to dimerization and that hyperactive JAK2 mutants promote dimerization, consistent with the model that dimerization triggers activation.
Science, this issue p. 643
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.
- Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2) – Science Magazine
- England coronavirus testing has not risen fast enough – science chief – The Guardian
- Coronavirus Tests Science’s Need for Speed Limits – The New York Times
- Trump Falsely Distorts New York Times COVID-19 Science Story – FactCheck.org
- This is the brightest supernova ever seen – Science Magazine
- Coronavirus Today: Science will save us – Los Angeles Times
- Italians stuck at home are measuring light pollution for ‘science on the balcony’ – TechCrunch
- ‘Oumuamua might be a shard of a broken planet – Science News
- College of Arts and Science converts thriving academic programs to departments – Vanderbilt University News