title: Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Kai-En
authors.initials: KE
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Mei-Ju
authors.initials: MJ
authors.lastname: Wu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Ho
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Abirami
authors.initials: A
authors.lastname: Santhanam
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan. National Core Facility for Protein Structural Analysis, Academia Sinica, Taipei 11581, Taiwan.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Chou
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei 10717, Taiwan. tcmeng@gate.sinica.edu.tw ahjwang@gate.sinica.edu.tw.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Meng
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11581, Taiwan. National Core Facility for Protein Structural Analysis, Academia Sinica, Taipei 11581, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei 10717, Taiwan. Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11047, Taiwan. tcmeng@gate.sinica.edu.tw ahjwang@gate.sinica.edu.tw.
authors.forename: Andrew H J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000737:chemistry; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D048291:Mitogen-Activated Protein Kinase 12 / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D019798:Neopterin / Q000737:chemistry; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3 / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D014357:Trypsin / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D014461:Ultracentrifugation
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D010455:Peptides; D014443:Tyrosine; D019798:Neopterin; D005982:Glutathione Transferase; D048291:Mitogen-Activated Protein Kinase 12; C516656:PTPN3 protein, human; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D014357:Trypsin