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

• Published in: Science signaling 2014-10, Vol.7 (347), p.ra98-ra98
• Main Authors: Chen, Kai-En, Lin, Shu-Yu, Wu, Mei-Ju, Ho, Meng-Ru, Santhanam, Abirami, Chou, Chia-Cheng, Meng, Tzu-Ching, Wang, Andrew H J
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Antineoplastic Agents - chemistry; Cloning, Molecular; Cross-Linking Reagents - chemistry; Crystallography, X-Ray; Drug Design; Glutathione Transferase - metabolism; Humans; Mass Spectrometry; Mitogen-Activated Protein Kinase 12 - chemistry; Mutagenesis, Site-Directed; Neopterin - chemistry; PDZ Domains; Peptides - chemistry; Phosphorylation; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 3 - chemistry; Spectrometry, Mass, Electrospray Ionization; Substrate Specificity; Trypsin - chemistry; Tyrosine - chemistry; Ultracentrifugation
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.2005722

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.