Structural analysis of PTPN21 reveals a dominant-negative effect of the FERM domain on its phosphatase activity

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Protein tyrosine phosphatase N21 (PTPN21) is a member of the FERM domain-containing PTP family, crucial for cytoskeleton-associated cellular processes.
• PTPN21's phosphatase domain contains a WPE loop, unlike the canonical WPD loop, leading to assumptions of lacking catalytic activity, despite its known functions.
• Reconciling PTPN21's structural features with its biological roles necessitates understanding its catalytic activity and regulation.

Purpose of the Study:

• To elucidate the structural and biochemical basis of PTPN21 regulation.
• To investigate the interplay between the FERM and PTP domains of PTPN21.
• To understand the mechanism of PTPN21 regulation by oncogenic proteins like HPV18 E7.

Main Methods:

• Determination of the crystal structures of individual PTPN21 FERM and PTP domains, and the FERM-PTP complex.
• Biochemical analyses to assess PTPN21's catalytic activity and regulatory mechanisms.
• Investigation of the interaction between HPV18 E7 oncoprotein and PTPN21.

Main Results:

• PTPN21 exhibits weak catalytic activity and is autoinhibited through the association of its FERM domain with the PTP domain.
• Disruption of the FERM-PTP interaction leads to enhanced extracellular signal-regulated kinase (ERK) activation.
• The oncogenic HPV18 E7 protein binds to PTPN21 at the FERM domain binding site, suggesting a mechanism of FERM domain displacement.

Conclusions:

• PTPN21 is a catalytically weak, autoinhibited enzyme regulated by its FERM domain.
• The FERM-PTP interaction is critical for PTPN21's basal activity and regulation.
• HPV18 E7 may modulate PTPN21 activity by displacing the FERM domain, impacting cellular signaling pathways.