Structural basis of NMI-IFP35 domains and swapping phenomenon in IFP35-NID

Interferon Stimulated Genes (ISGs) construct innate immunity as the first line of defense against pathogenic invasion, yet they can also aggravate disease under uncontrollable conditions. NMI and IFP35 are a homologous pair of ISGs, which also have been identified as novel Damage Associated Molecular Patterns (DAMPs) factor and implicated in immune response, immune signaling regulation and inflammatory diseases. However, the structural information of their distinct domain, called NMI-IFP35 domain (NID) that shares limited homology with known protein families, still remains poorly understood. In this study, we present three crystal structures of NID from NMI and IFP35, two of which are non-swapped dimers and one domain swapped IFP35-NID octamer, illustrating conformational diversity which hints at diverse structural oligomerization of NID. Molecular dynamic simulation identifies critical residues within dimer interface through which oligomerization of NIDs is built up, and reveals that different types of turns foster hinge loop region for domain swapping. These findings advance our understanding of the structure of NID domain and provide mechanistic insights into how NMI and IFP35 form higher-order complex during innate immune response. In addition, these structures provide molecular basis for developing therapeutics for inflammatory diseases targeting NMI and IFP35.