Importance of an N-terminal structural switch in the distinction between small RNA-bound and free ARGONAUTE.

ARGONAUTE (AGO) proteins bind to small non-coding RNAs to form RNA-induced silencing complexes. In the RNA-bound state, AGO is stable while RNA-free AGO turns over rapidly. Molecular features unique to RNA-free AGO that allow its specific recognition and degradation remain unknown. Here, we identify a confined, linear region in Arabidopsis AGO1 and human Ago2, the N-coil, as a structural switch with preferential accessibility in the RNA-free state. RNA-free Arabidopsis AGO1 interacts with the autophagy cargo receptor ATI1 by direct contact with specific N-coil amino acid residues whose mutation reduces the degradation rate of RNA-free AGO1 in vivo. The N-coil of human Ago2 has similar degron activity dependent on residues in positions equivalent to those required for the Arabidopsis AGO1-ATI1 interaction. These results elucidate the molecular basis for specific recognition and degradation of the RNA-free state of eukaryotic AGO proteins.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)