The receptor PTPRU is a redox sensitive pseudophosphatase

Area of Science:

• Molecular Biology
• Cell Signaling
• Enzymology

Background:

• Receptor-linked protein tyrosine phosphatases (RPTPs) control cellular phosphotyrosine levels, crucial for cell-cell communication.
• Most RPTPs have an active phosphatase domain (D1) and an inactive pseudophosphatase domain (D2).
• The specific roles and mechanisms of RPTPs in cellular signaling are areas of active research.

Purpose of the Study:

• To investigate the unique structural and functional characteristics of the RPTP PTPRU.
• To determine the catalytic activity and substrate-binding properties of PTPRU.
• To elucidate the mechanism by which PTPRU influences tyrosine phosphorylation pathways.

Main Methods:

• Biochemical assays to assess the catalytic activity of PTPRU's D1 domain against various phosphorylated substrates.
• Structural analysis to identify key features contributing to PTPRU's enzymatic properties.
• Substrate-binding experiments to evaluate PTPRU's interaction with known phosphatase substrates.

Main Results:

• PTPRU possesses two pseudophosphatase domains, distinguishing it from other RPTPs.
• The PTPRU-D1 domain lacks detectable catalytic activity due to structural rearrangements that occlude the active site and catalytic cysteine.
• Oxidation leads to disulfide bond formation involving a 'backdoor' cysteine, a known inactivation mechanism for phosphatases.
• Despite lacking activity, PTPRU binds substrates of active phosphatases, indicating a competitive inhibitory role.

Conclusions:

• PTPRU is a catalytically inactive pseudophosphatase, unique among the RPTP family.
• Its function in regulating tyrosine phosphorylation is mediated by substrate competition, not enzymatic activity.
• This discovery provides new insights into the complex regulatory networks of protein tyrosine phosphorylation.