Conformational reorganization and phase separation drive hyper-editing of ADR-2-ADBP-1 complex.

Adenosine deaminase acting on RNA (ADAR) proteins, which mediate adenosine-to-inosine editing of double-stranded ribonucleic acid (dsRNA) substrates, play essential roles in balancing innate immunity. Using cryogenic electron microscopy, we solved the structure of the Caenorhabditis elegans ADR-2-ADBP-1 complex (stoichiometric ratio, 2:2), which is an asymmetric ADR-2 dimer with one editing site blocked by the other ADR-2. Unexpectedly, dsRNA recruitment triggered dissociation of the ADR-2 dimer, exposing more competent dsRNA editing sites. Furthermore, high dsRNA and protein concentrations caused the formation of liquid-liquid phase-separated puncta, in which significantly greater editing activity was observed, indicating that organizational transitions enable the ADR-2-ADBP-1 complex to perform dsRNA hyper-editing. Our findings suggest that the ADAR editing mechanism adapts to different conditions via conformational reorganization.