Key result
AfAgo preferentially binds small RNA molecules with 5'-terminal AUU nucleotides and uses them as guides to target complementary DNA strands.
The study provides atomic details of the base-specific interactions of the short Argonaute protein AfAgo with guide and target strands, broadening the known mechanisms of Argonaute-nucleic acid recognition.
Preclinical AfAgo data; extends Argonaute-nucleic acid recognition mechanisms but leaves clinical translation open.
Argonaute (Ago) proteins are found in all three domains of life. The best-characterized group is eukaryotic Argonautes (eAgos). Being the structural core of RNA interference machinery, they use guide RNA molecules for RNA targeting. Prokaryotic Argonautes (pAgos) are more diverse, both in terms of structure (there are eAgo-like ‘long’ and truncated ‘short’ pAgos) and mechanism, as many pAgos are specific for DNA, not RNA guide and/or target strands. Some long pAgos act as antiviral defence systems. Their defensive role was recently demonstrated for short pAgo-encoding systems SPARTA and GsSir2/Ago, but the function and action mechanisms of all other short pAgos remain unknown. In this work, we focus on the guide and target strand preferences of AfAgo, a short Argonaute protein encoded by an archaeon Archaeoglobus fulgidus. We demonstrate that AfAgo associates with small RNA molecules carrying 5′-terminal AUU nucleotides in vivo, and characterize its affinity to various RNA and DNA guide/target strands in vitro. We also present X-ray structures of AfAgo bound to oligoduplex DNAs that provide atomic details for base-specific AfAgo interactions with both guide and target strands. Our findings broaden the range of currently known Argonaute-nucleic acid recognition mechanisms.
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Manakova et al. (2022) studied this question. AfAgo protein was evaluated on Binding affinity (Kd) to nucleic acids. AfAgo preferentially binds small RNA molecules with 5'-terminal AUU nucleotides and uses them as guides to target complementary DNA strands.
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