NAC guides a ribosomal multienzyme complex for nascent protein processing

• 成果类型: Article
• 署名作者: Lentzsch, Alfred M.; Yudin, Denis; Gamerdinger, Martin; Chandrasekar, Sowmya; Rabl, Laurenz; Scaiola, Alain; Deuerling, Elke; Ban, Nenad; Shan, Shu-ou
• 署名单位: California Institute of Technology; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Konstanz
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4251
• DOI: 10.1038/s41586-024-07846-7
• 发表日期: 2024-09-19
• 页码: 718-724
• 关键词: n-terminal acetylation; acetyltransferase; yeast; nata; CONSERVATION; specificity; chaperone; blocking

摘要

Approximately 40% of the mammalian proteome undergoes N-terminal methionine excision and acetylation, mediated sequentially by methionine aminopeptidase (MetAP) and N-acetyltransferase A (NatA), respectively(1). Both modifications are strictly cotranslational and essential in higher eukaryotic organisms(1). The interaction, activity and regulation of these enzymes on translating ribosomes are poorly understood. Here we perform biochemical, structural and in vivo studies to demonstrate that the nascent polypeptide-associated complex(2,3) (NAC) orchestrates the action of these enzymes. NAC assembles a multienzyme complex with MetAP1 and NatA early during translation and pre-positions the active sites of both enzymes 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-4,K-5 (HYPK) 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.