Co-translational folding and assembly of protein complexes in health and disease

The folding of newly synthesized proteins to the native state is a major challenge in the crowded environment of the eukaryotic cell. Failure to achieve the native, functional fold can often lead to aberrant aggregation, characteristic of neurodegenerative diseases. At the critical intersection of translation and folding, the ribosome is emerging as a hub, coordinating the activity of various factors guiding polypeptide chain folding. These include targeting factors, modifying enzymes as well as folding chaperones. However, little is known about the mechanisms facilitating the final step of folding, the assembly of polypeptides into oligomeric complexes. To capture co-translational events, in vivo, we utilized a ribosome profiling approach. This approach revealed that many complexes in eukaryotes are assembling already during synthesis. Folding chaperones coordinate assembly by protecting partially synthesized domains from premature interactions with partner subunits. As soon as the interface domain has emerged from the ribosome exit tunnel, it is engaged by a dedicated partner subunit in the complex. These dedicated subunits direct the folding and assembly of the entire complex, in a chaperone-like manner. Imaging analysis revealed co-localization of various mRNAs encoding for subunits in complex-specific cytoplasmic foci. We suggest spatial confinement of mRNA translation and co-translational subunit interactions can couple synthesis with protein assembly in eukaryotes. Our study shows that co-translational subunit association is a prevalent mechanism for the assembly of hetero-oligomers in yeast and indicates that translation, folding and the assembly of protein complexes are integrated processes in eukaryotes.