Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
Amino Acid Substitution
/ genetics
Carcinogenesis
/ genetics
Cell Membrane
/ chemistry
HeLa Cells
Humans
Janus Kinase 2
/ antagonists & inhibitors
Ligands
Microscopy, Fluorescence
Models, Molecular
Mutation
Nitriles
Phenylalanine
/ genetics
Protein Multimerization
Pyrazoles
/ pharmacology
Pyrimidines
Receptors, Erythropoietin
/ chemistry
Receptors, Somatotropin
/ chemistry
Receptors, Thrombopoietin
/ chemistry
Signal Transduction
Single Molecule Imaging
Valine
/ genetics
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
07 02 2020
07 02 2020
Historique:
received:
12
12
2018
revised:
08
10
2019
accepted:
20
12
2019
entrez:
8
2
2020
pubmed:
8
2
2020
medline:
17
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32029621
pii: 367/6478/643
doi: 10.1126/science.aaw3242
pmc: PMC8117407
mid: NIHMS1694456
doi:
Substances chimiques
Ligands
0
Nitriles
0
Pyrazoles
0
Pyrimidines
0
Receptors, Erythropoietin
0
Receptors, Somatotropin
0
Receptors, Thrombopoietin
0
Phenylalanine
47E5O17Y3R
ruxolitinib
82S8X8XX8H
Janus Kinase 2
EC 2.7.10.2
Valine
HG18B9YRS7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
643-652Subventions
Organisme : European Research Council
Pays : International
Organisme : NIAID NIH HHS
ID : R37 AI051321
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI101256
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI051321
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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