Protein domains are small structurally independent units that are part of a single amino acid chain. Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.

A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to form functionally distinct molecules in a process known as domain shuffling. The tertiary protein structure of evolutionarily related proteins is often more similar than the primary amino acid sequence; therefore, analyzing the three-dimensional structure of a protein domain, in addition to its sequence, is essential to study protein domain conservation.

The Argonaute protein family has three essential, conserved domains – PAZ, MID, and PIWI. These proteins have highly specialized binding modules that associate with small RNA components, including microRNAs, short interfering RNAs, and Piwi-interacting RNAs, to participate in gene silencing regulation. These small RNAs silence gene function only when they associate with Argonaute proteins. The PAZ domain’s characteristic feature is the binding pocket for the 3’-protruding end of the small RNAs. The PIWI domain, a domain that exhibits slicer activity, is structurally similar to bacterial RNase H, a protein responsible for hydrolyzing RNA in an RNA-DNA complex. The MID domain is present between the PAZ and PIWI domain and has a binding pocket for 5′ phosphate of the small RNA. One of the conserved motifs in these domains is the aspartic acid-aspartic acid-histidine (DDH) motif that participates in its catalytic function.

Argonaute proteins are conserved across organisms and have multiple families in different organisms ranging from five inDrosophila, eight in humans, ten inArabidopsis, and twenty-seven inC. elegans.