Yagmur POYRAZ, Ece OZCICEK, Zeynep KAVALCI, Sebnem ESSIZ
The European Chemistry and Biotechnology Journal - 2026;3(5):1-13
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. When STING is in the activated state, it captures TBK1, and both STING and IRF3 get phosphorylated after this step. Thus, STING doesn't only interact with TBK1 but also recruits IRF3 to TBK1. This process indicates that STING functions as a scaffold protein, guiding and supporting TBK1's phosphorylation of IRF3. STING has a long C-terminal tail that interacts with TBK1 and plays a crucial structural and functional role in regulating innate immune responses. However, how CTT interacts with TBK1 has some missing structural information. In this study, we performed molecular dynamics (MD) simulations to investigate the importance of the CTT loop for STING activation by comparing the molecular interactions within STING in the inactive and active states. We integrated the findings of previous loop modeling studies into our simulations. Namely, two independent runs of 320-nanosecond MD simulations for active and inactive structures with CTT loop structures have been analyzed, concentrating on the differences in CTT tail dynamics. RMSD and RMSF analyses of the trajectories displayed more stability and less flexibility for the active structure. Additionally, in the active structure, the CTT region is shown to be less flexible after forming an additional secondary structure of a small alpha-helix. The intricate structure of STING and TBK1, particularly with the complete C-terminal tail (CTT) region, remains elusive. Our study provides a fresh perspective on the potential STING-CTT and TBK1 interaction by proposing a model that reveals a possible small helix formation in the loop region.
