Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation

Kai En Chen, Shu Yu Lin, Mei Ju Wu, Meng Ru Ho, Abirami Santhanam, Chia Cheng Chou, Tzu Ching Meng, Andrew H.J. Wang

研究成果: 雜誌貢獻文章同行評審

14 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)ra98
期刊Science Signaling
7
發行號347
DOIs
出版狀態已發佈 - 10月 14 2014

ASJC Scopus subject areas

  • 生物化學
  • 分子生物學
  • 細胞生物學

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