期刊
SCIENCE SIGNALING
卷 7, 期 347, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005722
关键词
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资金
- Institute of Biological Chemistry at Academia Sinica
- National Program for Biopharmaceuticals (NRPB) [NSC 10102325-B-492-001]
The mitogen-activated protein kinase p38 gamma (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-p38 gamma 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 p38 gamma. The solution structure revealed the formation of an active-state complex between p38 gamma 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 p38 gamma. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38 gamma. Our findings may enable structure-based drug design targeting the PTPN3-p38 gamma interaction as an anticancer therapeutic.
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