Regulation of the catalytic activity of the human phosphatase PTPN4 by its PDZ domain

FEBS J. 2014 Nov;281(21):4852-65. doi: 10.1111/febs.13024. Epub 2014 Sep 30.

Abstract

The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cells death. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We demonstrate here that the PDZ domain inhibits the phosphatase activity of PTPN4. The mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We combined analytical ultracentrifugation, small angle X-ray scattering and NMR to understand how the PDZ domain controls PTPN4 activity. We show that the physiologically active PTPN4 two-domain, encompassing the PDZ and the phosphatase domains, adopts a predominant compact conformation in solution. The PDZ ligand binding restores the catalytic competence of PTPN4 disrupting the transient interdomain communication. This study strengthens the emerging notion that PDZ domains can act as regulators of enzyme activity and therefore are active players in the dynamic regulation of signaling pathways.

Keywords: PDZ domain; enzymology; intramolecular regulation; protein dynamics; protein tyrosine phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • PDZ Domains
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 4 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 4 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 4 / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Scattering, Small Angle
  • Signal Transduction
  • Solutions
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Ligands
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Solutions
  • PTPN4 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 4