REXO5

Model summary

A soluble nuclear exoribonuclease that uses an RNase H-like catalytic core and tandem RNA-recognition motifs to bind and degrade structured nuclear RNAs from their 3′ ends. It contributes to nuclear RNA surveillance by trimming and degrading small nuclear and related noncoding RNAs, operating prominently within nucleolar subdomains and broader nuclear compartments. Its RNA-binding surfaces guide substrates into a metal-dependent active site, coordinating with nuclear ribonucleoprotein assemblies and occasionally appearing in extracellular vesicles through RNA–protein complex trafficking.

Predicted Gene Ontology terms

1. 01

   I begin by dissecting the InterPro architecture and its order along the sequence.

   The N-terminal half is dominated by an RNase H-like core: IPR036397 (Ribonuclease H superfamily, residues 223–399) and IPR012337 (Ribonuclease H-like superfamily, residues 228–380) overlap with IPR013520 (Ribonuclease H-like domain, residues 227–385) and IPR034922 (RNA exonuclease 1-like, exonuclease domain, residues 229–377). This cluster defines a classical RNase H-like fold that coordinates divalent metal ions to catalyze 3′→5′ exonucleolytic cleavage of RNA. The presence of IPR047021 (RNA exonuclease REXO1/REXO3/REXO4-like family, residues 53–392) extends this assignment by placing the enzyme within the REXO1/3/4 clade of nuclear RNA exonucleases, which specialize in endogenous RNA surveillance.

2. 02

   The C-terminal half transitions into RNA-recognition and binding modules.

   IPR000504 (RNA recognition motif domain, residues 505–579) and a second RRM signature IPR000504 (residues 600–676) together create tandem RNA-binding surfaces that position and stabilize structured RNAs for processive decay. This region is reinforced by IPR035979 (RNA-binding domain superfamily, residues 505–664) and two overlapping alpha–beta plait superfamily signatures, IPR012677 (Nucleotide-binding alpha–beta plait domain superfamily, residues 491–581) and IPR012677 (residues 590–675), which describe the β–α–β architecture that scaffolds RRM-mediated nucleic acid binding. The ordered architecture—an N-terminal RNase H-like catalytic core followed by tandem RRMs—causally establishes a 3′→5′ exoribonuclease that binds and processes structured nuclear RNAs.

3. 03

   From this architecture, the molecular function resolves as a metal-dependent exonuclease that trims RNA from the 3′ end.

   The RNase H-like catalytic center supplies the chemistry, while the RRMs confer specificity and processivity through RNA engagement. This mechanistic layout supports a primary role in RNA turnover and surveillance. Such enzymes typically act on abundant nuclear substrates, and the tandem RRM arrangement is well-suited to recognize and degrade structured small nuclear and noncoding RNAs.

4. 04

   This catalytic–binding architecture naturally drives the biological process of snRNA catabolic process (GO:0016077).

   The enzyme’s nuclear specialization and REXO-family identity align with controlled decay of snRNAs and associated small nuclear/nucleolar species. By trimming and degrading these RNAs, the enzyme contributes to nuclear RNA quality control and turnover.

5. 05

   Cellular localization follows from function and binding modules.

   The absence of transmembrane features and the strong nuclear specialization point to a soluble nuclear enzyme. The nucleolus (GO:0005730) emerges as a logical subcompartment because snRNA and snoRNA pathways intersect there; tandem RRMs often target nucleolar RNPs for surveillance. The presence in extracellular exosome (GO:0070062) can be rationalized by the enzyme’s association with RNA–protein assemblies that are packaged into exosomes; nuclear RNA decay factors are frequently detected in extracellular vesicles as cargo or transient interactors.

6. 06

   Mechanistically, I hypothesize that the RNase H-like core binds two divalent metal ions to hydrolyze the 3′ end of snRNAs and related precursors, while the tandem RRMs clamp RNA and guide it into the active site.

   This arrangement enables selective decay within nuclear RNP granules and nucleolar subdomains. Likely interaction partners include nuclear exosome components and RNA-binding adaptors that route substrates to decay. I therefore anticipate transient assemblies with the nuclear exosome (EXOSC subunits), the MTR4 helicase, and nucleolar RNP factors such as fibrillarin and nucleolin, which together position structured snRNA substrates for efficient 3′→5′ degradation and coordinate their packaging into vesicles when appropriate.