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The ribosome is a major cellular machine that converts genetic information into biological function. Emerging data show that the ribosome is not only a protein synthesis machine, but also participates in the maturation of the nascent protein into properly folded and active molecules. The ribosome surface near the opening of the polypeptide exit tunnel can interact directly with the newly synthesized proteins and, more importantly, provides a platform where numerous protein biogenesis factors assemble, gain access to the nascent chain, and direct them into diverse biogenesis pathways. In this article, we review the current understanding of cotranslational protein maturation pathways, with an emphasis on systems in which biochemical studies provided a high-resolution molecular understanding and yielded generalizable mechanistic principles. 

Approximately 40% of the mammalian proteome undergoes N-terminal methionine excision and acetylation, mediated sequentially by methionine aminopeptidase (MetAP) and N-acetyltransferase A (NatA), respectively1. Both modifications are strictly cotranslational and essential in higher eukaryotic organisms1. The interaction, activity, and regulation of these enzymes on translating ribosomes are poorly understood. Here, biochemical, structural, and in vivo studies show that the nascent polypeptide-associated complex (NAC)2,3 orchestrates the action of these enzymes. NAC assembles a multienzyme complex with MetAP1 and NatA early during translation and pre-positions both enzyme active sites for timely sequential processing of the nascent protein. NAC further releases the inhibitory interactions from the NatA regulatory protein Huntingtin-Yeast-two-hybrid-Protein-K (HYPK)4,5 to activate NatA on the ribosome, enforcing cotranslational N-terminal acetylation. Our results provide a mechanistic model for the cotranslational processing of proteins in eukaryotic cells.