Research ArticleStructural Biology

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

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Science Signaling  14 Oct 2014:
Vol. 7, Issue 347, pp. ra98
DOI: 10.1126/scisignal.2005722

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Structural Insights into Kinase and Phosphatase Regulation

Unlike other members of the p38 family of kinases, p38γ has a PDZ-interacting motif. Phosphorylation of a tyrosine and a threonine in the kinase domain activates p38γ. The PDZ domain of the tyrosine phosphatase PTPN3 interacts with p38γ and is important for efficient dephosphorylation and inactivation of this kinase. Although Chen et al. discovered that the phosphatase domain of PTPN3 was sufficient to interact with dually phosphorylated p38γ, an interaction between the PDZ domain of PTPN3 and the PDZ-interacting motif of p38γ stabilized the complex and relieved an autoinhibitory intramolecular conformation of PTPN3. Structural analysis identified an invariant arginine in PTPN3 that interacted with the phosphorylated threonine in p38γ, suggesting that dephosphorylation of tyrosine by PTPN3 precedes dephosphorylation of threonine. These findings reveal new insight into the reciprocal allosteric regulation of PTPN3 and p38γ activity.

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