eRF3

Eukaryotic release factor 3 (eRF3) is a cytoplasmic GTP-binding protein that participates in translation termination in eukaryotes. It forms a functional complex with eRF1 and, in the presence of GTP, promotes the hydrolysis of the peptidyl-tRNA bond at stop codons UAA, UAG, and UGA, leading to release of the nascent polypeptide and disassembly of the ribosome.

eRF3 has a modular structure with an N-terminal domain that is highly variable among species and often engages with poly(A)-binding protein (PABP) and other factors, and a C-terminal GTPase domain that is evolutionarily related to elongation factors such as EF-Tu and eEF1A. The C-terminal domain binds and hydrolyzes GTP, and this hydrolysis is coordinated with stop-codon recognition by eRF1 to drive termination.

Most organisms harbor a single eRF3, but vertebrates commonly possess two paralogs, GSPT1 (eRF3A) and GSPT2 (eRF3B). eRF3A is typically the major cytoplasmic release factor, while eRF3B may have tissue- or development-specific roles in some species.

In addition to its canonical role in termination, eRF3 participates in mRNA quality control pathways. The eRF3–eRF1 complex interacts with PABP and can influence nonsense-mediated decay (NMD) and mRNA stability. In Saccharomyces cerevisiae, the eRF3 homolog is Sup35; in the prion state [PSI+], Sup35 aggregates, reducing termination efficiency and increasing stop-codon read-through, which can generate phenotypic diversity.