Dynamics of C-terminal tail of human STING structure, active and inactive conformations

The Stimulator of Interferon Genes (STING) protein is a transmembrane protein encoded by the STING1 gene. It is a critical component of the innate immune system, which serves as a sensor for cytosolic DNA and plays a crucial role in activating the Type-I interferon pathway. The enzyme cyclic GMP-AMP synthase (cGAS) binds to DNA and assists in the synthesis of cyclic GMP-AMP (cGAMP) from GTP and ATP. This reaction stimulates the activation of TANK-binding kinase 1 (TBK1), an enzyme involved in signaling pathways that result in the phosphorylation of STING. The interaction between STING, TBK1, and IRF3 selectively interferes with IRF3 phosphorylation without obstructing TBK1 activation, leading to mutations in STING. This process indicates that STING functions as a scaffold protein, guiding and supporting TBK1’s phosphorylation of IRF3. IRF3 activation occurs when STING’s C-terminal tail (CTT) binds to IRF3, leading to conformational change. STING’s CTT tail plays a crucial structural and functional role in regulating innate immune responses. Understanding the structure of the CTT loop is vital for unraveling the mechanism of STING-mediated signaling. In this study, we performed molecular dynamics (MD) simulations to investigate the importance of the CTT loop for STING activation through comparing the molecular interactions within STING-TBK1 complexes in their inactive and active states. We integrated the findings of previous modeling studies into our simulations.