Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.
Science
; 367(6478): 643-652, 2020 02 07.
Article
em En
| MEDLINE
| ID: mdl-32029621
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores da Somatotropina
/
Membrana Celular
/
Receptores da Eritropoetina
/
Janus Quinase 2
/
Receptores de Trombopoetina
/
Multimerização Proteica
/
Carcinogênese
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article