Abstract
Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.
Highlights
Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death
We previously showed that PTPN4 prevents the induction of cell death in glioblastoma cell lines in a PDZ-PDZ ligand dependent manner[10]
We showed that the PDZ domain of PTPN4 inhibits the phosphatase activity, while a PBM bound to the PDZ domain abrogates the auto-inhibition of the catalytic activity of PTPN411, 13
Summary
Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. PTPN4 (UniProt P29074) is a large modular protein containing a N-terminal FERM (Band 4.1, Ezrin, Radixin, and Moesin) domain, a PDZ (PSD-95/Dlg/ZO-1) domain and a C-terminal catalytic tyrosine phosphatase domain (Fig. 1). The PBM of p38γ has the highest affinity of all PBM from endogenous partners of PTPN4 and has a similar affinity to the optimized pro-death 13-amino acids peptide Cyto8-RETEV Both peptides are efficient inducers of cell death after their intracellular delivery[11, 12]. We showed that the PDZ domain of PTPN4 inhibits the phosphatase activity, while a PBM bound to the PDZ domain abrogates the auto-inhibition of the catalytic activity of PTPN411, 13
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