Molecular recognition of ITIM/ITSM domains with SHP2 and their allosteric effect

Cheng, Yan; Ouyang, Weiwei; Liu, Ling; Tang, Lingkai; Zhang, Zhigang; Yue, Xinru; Liang, Li; Hu, Jianping; Luo, Ting

doi:10.1039/d3cp03923d

Cited by 2 publications

(1 citation statement)

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“…Phosphorylated ITIMs are recognized for their ability to interact with SH2 domains within proteins, which can trigger downstream signaling events [26]. Tyr241 and Tyr263 embedded in the ITIMs are responsible for the tyrosine phosphorylation of PZR, providing docking sites for the enzyme, for example, responsible for the binding of SHP2.…”

Section: Workflowmentioning

confidence: 99%

Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics

Gao,

Xing,

2024

Molecules

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Phosphorylation of tyrosine is the basic mode of protein function and signal transduction in organisms. This process is regulated by protein tyrosine kinases (PTKs) and protein tyrosinases (PTPs). Immunoreceptor tyrosine-based inhibition motif (ITIM) has been considered as regulating the PTP activity through the interaction with the partner proteins in the cell signal pathway. The ITIM sequences need to be phosphorylated first to active the downstream signaling proteins. To explore potential regulatory mechanisms, the ITIM sequences of two transmembrane immunoglobulin proteins, myelin P0 protein-related protein (PZR) and programmed death 1 (PD-1), were analyzed to investigate their interaction with proteins involved in regulatory pathways. We discovered that phosphorylated ITIM sequences can selectively interact with the tyrosine phosphatase SHP2. Specifically, PZR-N-ITIM (pY) may be critical in the interaction between the ITIM and SH2 domains of SHP2, while PD1-C-ITSM (pY) may play a key role in the interaction between the ITIM and SH2 domains of SHP2. Quite a few proteins were identified containing the SH2 domain, exhibiting phosphorylation-mediated interaction with PZR-ITIM. In this study, 14 proteins with SH2 structural domains were identified by GO analysis on 339 proteins associated to the affinity pull-down of PZR-N-ITIM (pY). Through the SH2 domains, these proteins may interact with PZR-ITIM in a phosphorylation-dependent manner.

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Section: Workflowmentioning

confidence: 99%

Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics

Gao,

Xing,

2024

Molecules

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Study on SHP2 Conformational Transition and Structural Characterization of Its High-Potency Allosteric Inhibitors by Molecular Dynamics Simulations Combined with Machine Learning

Wujieti,

Hao,

Liu

et al. 2024

Molecules

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The src-homology 2 domain-containing phosphatase 2 (SHP2) is a human cytoplasmic protein tyrosine phosphatase that plays a crucial role in cellular signal transduction. Aberrant activation and mutations of SHP2 are associated with tumor growth and immune suppression, thus making it a potential target for cancer therapy. Initially, researchers sought to develop inhibitors targeting SHP2’s catalytic site (protein tyrosine phosphatase domain, PTP). Due to limitations such as conservativeness and poor membrane permeability, SHP2 was once considered a challenging drug target. Nevertheless, with the in-depth investigations into the conformational switch mechanism from SHP2’s inactive to active state and the emergence of various SHP2 allosteric inhibitors, new hope has been brought to this target. In this study, we investigated the interaction models of various allosteric inhibitors with SHP2 using molecular dynamics simulations. Meanwhile, we explored the free energy landscape of SHP2 activation using enhanced sampling technique (meta-dynamics simulations), which provides insights into its conformational changes and activation mechanism. Furthermore, to biophysically interpret high-dimensional simulation trajectories, we employed interpretable machine learning methods, specifically extreme gradient boosting (XGBoost) with Shapley additive explanations (SHAP), to comprehensively analyze the simulation data. This approach allowed us to identify and highlight key structural features driving SHP2 conformational dynamics and regulating the activity of the allosteric inhibitor. These studies not only enhance our understanding of SHP2’s conformational switch mechanism but also offer crucial insights for designing potent allosteric SHP2 inhibitors and addressing drug resistance issues.

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Molecular recognition of ITIM/ITSM domains with SHP2 and their allosteric effect

Abstract: The Src homology-2 (SHP2) is a non-receptor protein tyrosine phosphatase, composed of N-SH2, C-SH2, and PTP domains, which are widely expressed in various cells. SHP2 regulates the immune response through...

Cited by 2 publications

References 84 publications

Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics

Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics

Study on SHP2 Conformational Transition and Structural Characterization of Its High-Potency Allosteric Inhibitors by Molecular Dynamics Simulations Combined with Machine Learning

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