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Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
- Source :
-
Science (New York, N.Y.) [Science] 2020 Feb 07; Vol. 367 (6478), pp. 643-652. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Amino Acid Substitution genetics
HeLa Cells
Humans
Janus Kinase 2 antagonists & inhibitors
Ligands
Microscopy, Fluorescence
Models, Molecular
Mutation
Nitriles
Phenylalanine genetics
Pyrazoles pharmacology
Pyrimidines
Signal Transduction
Single Molecule Imaging
Valine genetics
Carcinogenesis genetics
Cell Membrane chemistry
Janus Kinase 2 chemistry
Janus Kinase 2 genetics
Protein Multimerization
Receptors, Erythropoietin chemistry
Receptors, Somatotropin chemistry
Receptors, Thrombopoietin chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 367
- Issue :
- 6478
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 32029621
- Full Text :
- https://doi.org/10.1126/science.aaw3242