Interaction Between HAQ-STING Mutation and COPA: Protection Against COPA Syndrome.

backgroundCOPA syndrome is a rare autoinflammatory disorder caused by mutations in the COPA gene, leading to immune dysregulation and inflammatory pathology. The HAQ variant of stimulator of interferon genes (STING) allele has been identified as a protective factor against disease manifestation. Understanding the molecular interaction between HAQ-STING and COPA is critical for uncovering potential therapeutic strategies.

methodsThis study utilized AlphaFold2 Multimer (AF2M) (DeepMind, London, UK) an extension of AlphaFold2 designed to predict the structures of protein complexes (multimers), to analyze the structural interaction between COPA, STING, and HAQ-STING. PyMOL (Schrödinger, Inc., New York, USA) was used for molecular visualization and analysis of conformational differences in protein-protein interactions (PPIs). Structural alignment and binding pocket analysis were conducted to assess the potential impact of HAQ-STING on COPA function. Molecular docking studies were conducted with AutoDock Vina Extended (OneAngstrom, Grenoble, France).

resultsAF2M analysis revealed that HAQ-STING causes a 90-degree rotational shift in its binding orientation to COPA compared to STING, inducing significant conformational rearrangements. The interaction alters COPA's structural stability, suggesting an allosteric regulatory mechanism. A potential binding channel for a small therapeutic molecule was identified at the interface of STING and COPA. If the channel in the COPA STING interface meets criteria for depth, stability, and functional significance, it could be a drug-binding pocket. A therapeutic small molecule docked in a binding pocket at the interface of two interacting proteins can disrupt the protein-protein complex. This approach, known as PPI inhibition, is a well-established strategy in drug discovery. Fosfomycin, a phosphate-containing molecule, docked in the channel at the interface of COPA and STING.

conclusionThis study provides novel structural insights into the protective role of HAQ-STING in COPA syndrome. The conformational shift induced by HAQ-STING may modulate immune signaling, preventing disease manifestation. A potential binding channel for a small therapeutic molecule was identified at the interface of STING and COPA; fosfomycin was docked in this channel. These findings highlight potential therapeutic avenues, including gene therapy, small-molecule inhibitors, and STING pathway modulation. Further experimental validation is needed to translate these structural insights into clinical applications.