Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation.
Sci Signal
; 7(347): ra98, 2014 Oct 14.
Article
en En
| MEDLINE
| ID: mdl-25314968
ABSTRACT
The mitogen-activated protein kinase p38γ (also known as MAPK12) and its specific phosphatase PTPN3 (also known as PTPH1) cooperate to promote Ras-induced oncogenesis. We determined the architecture of the PTPN3-p38γ complex by a hybrid method combining x-ray crystallography, small-angle x-ray scattering, and chemical cross-linking coupled to mass spectrometry. A unique feature of the glutamic acid-containing loop (E-loop) of the phosphatase domain defined the substrate specificity of PTPN3 toward fully activated p38γ. The solution structure revealed the formation of an active-state complex between p38γ and the phosphatase domain of PTPN3. The PDZ domain of PTPN3 stabilized the active-state complex through an interaction with the PDZ-binding motif of p38γ. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38γ. Our findings may enable structure-based drug design targeting the PTPN3-p38γ interaction as an anticancer therapeutic.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Proteína Quinasa 12 Activada por Mitógenos
/
Proteína Tirosina Fosfatasa no Receptora Tipo 3
/
Dominios PDZ
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Taiwán