Lehrer, S.

Background: COPA disease is a rare autoinflammatory disorder caused by mutations in the COPA gene, leading to immune dysregulation and inflammatory pathology. The HAQ 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. Methods: This study utilized AlphaFold2 Multimer to predict the structural interaction between COPA, STING, and HAQ STING. PyMOL was used for molecular visualization and analysis of conformational differences in protein-protein interactions. Structural alignment and binding pocket analysis were conducted to assess the potential impact of HAQ STING on COPA function. Results: AlphaFold2 Multimer 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. Two large potential binding holes were identified in the WD40 domain, which could serve as potential targets for small-molecule drug development. Conclusion: This study provides novel structural insights into the protective role of HAQ STING in COPA disease. The conformational shift induced by HAQ STING may modulate immune signaling, preventing disease manifestation. 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.