NAC guides a ribosomal multienzyme complex for nascent protein processing

Alfred M. Lentzsch, Denis Yudin, Martin Gamerdinger, Sowmya Chandrasekar, Laurenz Rabl, Alain Scaiola, Elke Deuerling, Nenad Ban () and Shu-ou Shan ()
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Alfred M. Lentzsch: California Institute of Technology
Denis Yudin: ETH Zurich
Martin Gamerdinger: University of Konstanz
Sowmya Chandrasekar: California Institute of Technology
Laurenz Rabl: University of Konstanz
Alain Scaiola: ETH Zurich
Elke Deuerling: University of Konstanz
Nenad Ban: ETH Zurich
Shu-ou Shan: California Institute of Technology

Nature, 2024, vol. 633, issue 8030, 718-724

Abstract: Abstract 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 we perform biochemical, structural and in vivo studies to demonstrate that the nascent polypeptide-associated complex2,3 (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 K4,5 (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.

Date: 2024
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DOI: 10.1038/s41586-024-07846-7

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