Exploring the Allosteric Mechanism of Src Homology-2 Domain-Containing Protein Tyrosine Phosphatase 2 (SHP2) by Molecular Dynamics Simulations.

Quan Wang,Wen-Cheng Zhao,Xue-Qi Fu,Qing-Chuan Zheng

doi:10.3389/fchem.2020.597495

Abstract

The Src homology-2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2, encoded by PTPN11) is a critical allosteric phosphatase for many signaling pathways. Programmed cell death 1 (PD-1) could be phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and can bind to SHP2 to initiate T cell inactivation. Although the interaction of SHP2-PD-1 plays an important role in the immune process, the complex structure and the allosteric regulation mechanism remain unknown. In this study, molecular dynamics (MD) simulations were performed to study the binding details of SHP2 and PD-1, and explore the allosteric regulation mechanism of SHP2. The results show that ITIM has a preference to bind to the N-SH2 domain and ITSM has almost the same binding affinity to the N-SH2 and C-SH2 domain. Only when ITIM binds to the N-SH2 domain and ITSM binds to the C-SH2 domain can the full activation of SHP2 be obtained. The binding of ITIM and ITSM could change the motion mode of SHP2 and switch it to the activated state.

Highlights

Protein tyrosine phosphorylation is a common post-translational modification, which plays an important role in cellular signaling pathways
The Protein tyrosine phosphatases (PTPs) domain of SHP2 could keep a stable conformation in all systems, no matter whether SHP2 binds to immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) or not (Supplementary Figure 1)
SHP099 is the first successful allosteric inhibitor which binds to the interface of the three domains and anchors them as a “latch” (Chen et al, 2016; Garcia Fortanet et al, 2016)

Summary

Introduction

Protein tyrosine phosphorylation is a common post-translational modification, which plays an important role in cellular signaling pathways. Protein tyrosine phosphatases (PTPs) are in charge of removing the phosphate groups, accompanied by protein tyrosine kinases (PTKs), which adjust the homeostasis of tyrosine phosphorylation in cell. Dysregulation of phosphorylation and dephosphorylation can lead to various human diseases such as cancer (Cohen, 2000). PTKs have been successfully targeted many times to treat diseases (Bhullar et al, 2018). The Src homology-2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2, encoded by PTPN11) has been one of the hottest topics in the world and has attracted much attention to study the possibility in cancer (Mohi and Neel, 2007; Chan et al, 2008). SH2 and PTP domains are necessary for

Methods

Results

Conclusion