Lau, P.W. et al. Nat. Struct. Mol. Biol. 19, 436–440 (2012).

Primarily for its role in the silencing of genes via small RNAs, Dicer is an enzyme that fascinates biologists. Dicer proteins are large, complicated proteins that recognize double-stranded RNA (dsRNA) and chop it into precisely sized products. The structural and mechanistic details of how these activities are performed by different domains in this large protein remain largely unknown. Electron microscopy reconstructions of human Dicer have been reported, but Lau et al. set out to experimentally test working models of its domain architecture. They did so by introducing short amino-acid sequence tags targeted to specific functional domains in the protein. They purified the tagged proteins, visualized them by negative-stain electron microscopy and performed three-dimensional reconstructions. The strategy revealed the sites associated with different functional domains in the architecture of the large protein and allowed comparisons between different Dicer homologs, providing insight into the structural basis for small RNA production in eukaryotes.