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Published May 15, 2022 | v3
Journal Article Open

Ribosome-nascent Chain Interaction Regulates N-terminal Protein Modification

  • 1. ROR icon California Institute of Technology


Numerous proteins initiate their folding, localization, and modifications early during translation, and emerging data show that the ribosome actively participates in diverse protein biogenesis pathways. Here we show that the ribosome imposes an additional layer of substrate selection during N-terminal methionine excision (NME), an essential protein modification in bacteria. Biochemical analyses show that cotranslational NME is exquisitely sensitive to a hydrophobic signal sequence or transmembrane domain near the N terminus of the nascent polypeptide. The ability of the nascent chain to access the active site of NME enzymes dictates NME efficiency, which is inhibited by confinement of the nascent chain on the ribosome surface and exacerbated by signal recognition particle. In vivo measurements corroborate the inhibition of NME by an N-terminal hydrophobic sequence, suggesting the retention of formylmethionine on a substantial fraction of the secretory and membrane proteome. Our work demonstrates how molecular features of a protein regulate its cotranslational modification and highlights the active participation of the ribosome in protein biogenesis pathways via interactions of the ribosome surface with the nascent protein.

Additional Information

© 2022 Published by Elsevier. Received 28 December 2021, Revised 1 March 2022, Accepted 4 March 2022, Available online 10 March 2022, Version of Record 17 March 2022. We thank members of the Shan lab for discussions and comments on the manuscript. The E. coli strains CAG12184 and KPS73, and the plasmids pHUE and pHUsp2-cc are generous gifts from A. Varshavsky. This work was supported by NIH grant R35 GM136321 to S.S. and Think Global Education Trust Fellowship to C.I.Y. CRediT authorship contribution statement: Chien-I Yang: Conceptualization, Investigation, Formal analysis, Writing – original draft, Writing – review & editing. Jiwoo Kim: Investigation. Shu-ou Shan: Supervision, Writing – review & editing. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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October 19, 2023
October 19, 2023