Abstract

Recent studies have shown that the stimulator of interferon gene (STING) protein plays a central role in the immune system by facilitating the production of Type I interferons in cells. The STING signaling pathway is also a prominent activator of cancer-killing T cells that initiates a powerful adaptive immune response. Since biomolecular signaling pathways are complicated and not easily identified through traditional experiments, molecular dynamics (MD) has often been used to study these biological pathways’ structural and dynamical responses. Here, we carried out MD simulations for full-length chicken and human STING (chSTING and hSTING) proteins. Specifically, we investigated ligand-bound closed and ligand-unbound open forms of each STING in the membrane system by comparing conformational and dynamical differences among them. Our research provides clues for understanding the mechanism of the STING signaling pathway by uncovering some detailed insights for the examined systems: the residues from each chain in the binding pocket are strongly correlated to one another in the open STING structure compared with those in the closed STING structure. Ligand-bound closed STING displays approximately 170° rotation of the ligand-binding domain (LBD) relative to the open-STING structure. The detailed dynamical analysis of residue Cys148 in the linker region of hSTING does not support the earlier hypothesis that Cys148 can form disulfide bonds between adjacent STING dimers. We also reveal that using the full-length proteins is critical as the MD simulations of the LBD portion only cannot properly describe the global conformational properties of multiple domain proteins, such as STING.

Document Type

Article

Source Publication

ChemRxiv

Version

Pre-Print

Publication Date

2-2022

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Notice: This material may be protected by copyright law (Title 17 U.S. Code).

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