LAUSR

Argonaute proteins have a variety of functions ranging from post transcriptional gene silencing in eukaryotes to host defence in prokaryotic systems. Despite the well-established functional understanding of Argonautes, the biophysical understanding of its targeting mechanism remains limited. How is it able to find a specific nucleic acid sequence among numerous decoys? Here we make use of the high spatiotemporal resolution of single-molecule FRET to elucidate the target search mechanism of a mesophilic bacterial Argonaute. We find that it makes use of lateral diffusion for rapid sampling of adjacent sequences while using three-dimensional diffusion in order to cover larger distances efficiently. Similar results have been obtained for thermophilic bacterial Argonaute. The long-distance facilitated diffusion mechanism might be a conserved feature across different Argonaute families and may also be a general feature for other nucleic-acid guide directed nucleoproteins such as CRISPR systems.