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Assembly Factors and snoRNAs Manage Programmable RNA Folding and Misfolding to Support Growth in Stationary Phase

ABSTRACT: This research demonstrates how ribosomal RNA folding is actively controlled during 40S ribosome assembly to prevent a misfolding intermediate where helix h24 becomes mispositioned when bound by the protein Rrp5. We show that assembly factors Rrp36 and snoRNAs (snR31, snR54) cooperatively prevent this misfolding by tethering Rrp5 away from the platform and delaying h24 formation, respectively. Disrupting these interactions leads to widespread structural alterations that persist into mature ribosomes. Interestingly, we reveal that this misfolding pathway is not an evolutionary mistake but rather serves a physiological function. This work reframes assembly factors and snoRNAs as molecular chaperones that actively reshape the RNA folding landscape, with broader implications for understanding ribosome heterogeneity and conditional ribosome specialization.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE338022 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Folding of newly synthesized proteins to the native state is a major challenge within the crowded cellular environment, since non-productive interactions can lead to misfolding, aggregation and degradation1. Cells cope with this challenge by coupling synthesis with polypeptide folding and by employing molecular chaperones to safeguard folding already cotranslationally2. However, little is known about the final step of folding, the assembly of polypeptides into complexes, although most of the cellular proteome forms oligomeric assemblies3. In prokaryotes, a proof-of-concept study showed that assembly of heterodimeric luciferase is an organized cotranslational process, facilitated by spatially confined translation of the subunits encoded on a polycistronic mRNA4. In eukaryotes, however, fundamental differences such as rarity of polycistronic mRNAs and different chaperone constellations raise the question whether assembly is also coordinated with translation. Here we provide a systematic and mechanistic analysis of protein complex assembly in eukaryotes using ribosome profiling. We determined the in vivo nascent subunits interactions of 12 hetero-oligomeric protein complexes of Saccharomyces cerevisiae at near-residue resolution. We find 9 complexes assemble cotranslationally; the 3 complexes that do not show cotranslational interactions are regulated by dedicated assembly chaperones5-7. Cotranslational assembly often occurs uni-directionally, with one fully synthesized subunit engaging its nascent partner subunit(s), thereby counteracting its aggregation propensity. The onset of cotranslational subunit association coincides sharply with full exposure of the nascent interaction domain at the ribosomal tunnel exit. The action of the ribosome-associated Hsp70 chaperone Ssb8 is coordinated with assembly. Ssb transiently engages partially synthesized interaction domains, then dissociates before the onset of partner subunit association, presumably to prevent premature assembly interactions. Our study shows that cotranslational subunit association is a prevalent mechanism for hetero-oligomers assembly in yeast and indicates that translation, folding and assembly of protein complexes are integrated processes in eukaryotes.

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Assembly Factors and snoRNAs Manage Programmable RNA Folding and Misfolding to Support Growth in Stationary Phase

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