Evolution of Protein Folding and Assembly Pathways: Deciphering the Characteristics of Divergent Co-translational Assembly Pathways
Protein-protein interactions are at the heart of all cellular processes, with the ribosome emerging as a platform that orchestrates nascent-chain interplay dynamics. In this seminar, I will present a multidisciplinary study combining in vivo and in silico approaches to capture snapshots of the translation process through various methods, such as selective ribosome profiling, all-atom molecular dynamics simulations, and AlphaFold-based predictions. These approaches elucidate the interplay of ribosome-associated factors that guide the folding and assembly pathways of emerging polypeptide chains. Focusing on the divergent folding and assembly pathways of the N-terminal acetyltransferase complex family to gain mechanistic insight—and expanding the analysis to the proteome scale—we discovered that assembly is driven by high-energy interface ‘hotspots’ that anchor mutually stabilizing subunits. We further demonstrate that these structural signatures can accurately predict co-translational assembly across species and that disrupting these hotspots is linked to aggregation and neurodegenerative disease.
