Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix.
Biochem J
; 473(11): 1579-91, 2016 06 01.
Article
en En
| MEDLINE
| ID: mdl-27029346
ABSTRACT
The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild-type function.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Citocinas
/
Janus Quinasa 2
Límite:
Humans
Idioma:
En
Revista:
Biochem J
Año:
2016
Tipo del documento:
Article
País de afiliación:
Bélgica