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NAC guides a ribosomal multienzyme complex for nascent protein processing

Author

Listed:
  • 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)

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.

Suggested Citation

  • Alfred M. Lentzsch & Denis Yudin & Martin Gamerdinger & Sowmya Chandrasekar & Laurenz Rabl & Alain Scaiola & Elke Deuerling & Nenad Ban & Shu-ou Shan, 2024. "NAC guides a ribosomal multienzyme complex for nascent protein processing," Nature, Nature, vol. 633(8030), pages 718-724, September.
  • Handle: RePEc:nat:nature:v:633:y:2024:i:8030:d:10.1038_s41586-024-07846-7
    DOI: 10.1038/s41586-024-07846-7
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    Cited by:

    1. Jeonghyun Oh & Christy Catherine & Eun Seon Kim & Kwang Wook Min & Hae Chan Jeong & Hyojin Kim & Mijin Kim & Seung Hae Ahn & Nataliia Lukianenko & Min Gu Jo & Hyeon Seok Bak & Sungsu Lim & Yun Kyung K, 2025. "Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    2. Nina McTiernan & Ine Kjosås & Thomas Arnesen, 2025. "Illuminating the impact of N-terminal acetylation: from protein to physiology," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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