Phosphotyrosine couples peptide binding and SHP2 activation via a dynamic allosteric network

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• SHP2 is a crucial protein tyrosine phosphatase regulating cellular signaling pathways.
• Its activity is tightly controlled by phosphotyrosine (pY)-containing peptides.
• The auto-inhibited structure of SHP2 involves the N-terminal SH2 (N-SH2) domain blocking the catalytic site.

Purpose of the Study:

• To elucidate the mechanism by which pY-containing peptides activate SHP2.
• To investigate the role of allosteric communication in SHP2 regulation.
• To differentiate the regulatory roles of the N-SH2 and C-terminal SH2 (C-SH2) domains.

Main Methods:

• Structural analysis of SHP2 conformation and peptide binding.
• Investigation of protein dynamics and allosteric networks.
• Biochemical assays to assess SHP2 catalytic activity.

Main Results:

• pY recognition enhances N-SH2 loop dynamics through an allosteric network.
• This network destabilizes the N-SH2-PTP interaction, creating a binding pocket.
• Full phosphopeptide binding stabilizes the active SHP2 conformation.

Conclusions:

• An allosteric network within N-SH2 is essential for SHP2 activation.
• N-SH2 directly regulates SHP2 activity, while C-SH2 mediates phosphopeptide recruitment.
• Understanding this mechanism provides insights into SHP2-mediated signaling.