The various facets of the protein-folding activity of the ribosome

Abstract

In addition to its involvement in protein synthesis, the ribosome is implicated in protein folding. Some co-translational events, such as the rhythm of protein synthesis, the passage through the exit tunnel of the ribosome, or the interaction with ribosome-associated chaperones may help protein folding. Ribosomes from prokaryotes, eukaryotes, and mitochondria have also been shown to assist the folding of denatured proteins in vitro in a translation-independent way. This intriguing protein-folding activity of the ribosome (PFAR, also termed RPFA) has been mapped to the domain V of the large rRNA of the large subunit of the ribosome. Unfolded, newly synthesized proteins catalyze the dissociation of the two ribosomal subunits in vitro, thereby promoting ribosome recycling and facilitating accessibility of domain V to these proteins, which in turn may help their folding by PFAR. The recent identification of 6AP and GA - the two first drugs that specifically inhibit PFAR without affecting protein translation - will help decipher the biological significance of PFAR in vivo. Of note, 6AP and GA were initially isolated on the basis of their activity against prion-based diseases. Recently, 6AP and GA were also shown to be active in vivo in a drosophila model for oculopharyngeal muscular dystrophy, which is another amyloid-based disease. This effect is mimicked by large deletions in the ribosomal DNA (rDNA) locus. In addition, small deletions in the rDNA locus show a synergistic effect with low doses of 6AP and GA. Hence, PFAR may be involved in various amyloid-based diseases.