PUA domain

In molecular biology, the PUA domain is an ancient RNA-binding domain.

Structure

The PUA domain consists of 64-96 amino acids forming a compact alpha/beta fold. It shows six beta-strands and two alpha-helices that cap the structure.

Function

The PUA domain is found in diverse protein families involved in:RNA modification: pseudouridine synthases, archaeosine transglycosylases, RNA methyltransferasesRibosome biogenesis: H/ACA box ribonucleoproteins, telomerase complex componentsTranslation: eukaryotic initiation factorsMetabolism: glutamate kinases

RNA recognition mechanism

The PUA domain uses a distinctive "double-edged ledge" formed by the alpha1-beta2 loop and beta6 strand for RNA binding while an "adjacent cleft" alpha1-beta2 accommodates single-stranded RNA overhangs. It has two main binding modes: the sideways binding recognizes minor groove of double-stranded RNA stems; and the terminal binding recognizes the bottom/terminal end of RNA stems across the major groove.

Evolution and distribution

Proteins with the PUA domain are found across bacteria, archaea, and eukaryotes. This domain has evolved as a flexible RNA interaction module, with different proteins using variations in amino acid composition to achieve specific RNA recognition patterns while maintaining the core structural framework.

Clinical Relevance

PUA domain proteins are essential for fundamental cellular processes. Some examples of associated diseases are:

Mutations in the protein Dyskerin lead to telomere dysfunction
MCT1 is implicated in cancer through its role in cell proliferation
Nsun6 mutations can lead to intellectual disability