PUA domain

In molecular biology, the PUA domain (Pseudouridine synthase and Archaeosine transglycosylase domain) is an ancient RNA-binding domain.^[1]

PUA domain
Cartoon representation of the molecular structure of the crystal structure of the PUA domain-containing protein APE0525 from Aeropyrum pernix HB8 (PDB: 2cx1​)
Identifiers
Symbol	PUA
Pfam clan	CL0178
ECOD	1.1.9

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.^[2]

Function

The PUA domain is found in diverse protein families^[1] involved in:

• RNA modification: pseudouridine synthases, archaeosine transglycosylases, RNA methyltransferases
• Ribosome biogenesis: H/ACA box ribonucleoproteins, telomerase complex components
• Translation: eukaryotic initiation factors
• Metabolism: glutamate kinases (proline biosynthesis)

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.^[1]

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.^[1]

Clinical Relevance

PUA domain proteins are essential for fundamental cellular processes.^[2] Some examples of associated diseases are:

• Mutations in the protein Dyskerin lead to telomere dysfunction (dyskeratosis congenita)^[3]
• MCT1 is implicated in cancer through its role in cell proliferation^[4]
• Nsun6 mutations can lead to intellectual disability^[5]