Guide and passenger strand recognition by Argonaute protein

Argonaute protein is involved in RNAi, it recognizes and binds to siRNA duplex, cleaves and removes passenger strand, and allows guide strand to scan target mRNA.

Argonaute (AGO) proteins have 4 discrete folding units:

  1. N-terminal: Acts as a wedge.
  2. PAZ domain: contains a binding pocket, anchors the 2-nucleotide 3′ overhang of siRNA like duplex.
  3. MID domain: Binds to 5′-P of guide RNA.
  4. PIWI domain: Adopts a RNase H folds and 3 residues within PIWI domain, form a catalytic triad.

Both ends of the guide RNA remain stably bound to AGO protein. Now the question is how it differentiates guide strand (anti-sense) from passenger strand (sense)?

a. The MID domain consists of a Rossmann-like fold and interacts directly with the 5′-end of the guide strand by recognition of the phosphorylated first nucleotide and base features.

b. the MID domain of RsAgo (bacterial) forms base-specific interactions with the 5′-terminal uracil of the guide RNA strand. The aromatic residue Y463 stacked against the 5′-terminal uracil and the main chain of A454 formed a hydrogen bond with N3 of the uracil. Y463 is widely conserved across Argonaute proteins and this conserved tyrosine has also been shown to stack against the 5′-terminal base of the guide strand in other Argonaute proteins.

It means few features of guide strand are used for recognition by AGO.

Details- Structural basis for the recognition of guide RNA and target DNA heteroduplex by Argonaute

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