Early Scanning of Nascent Polypeptides inside the Ribosomal Tunnel by NAC

Mol Cell. 2019 Sep 5;75(5):996-1006.e8. doi: 10.1016/j.molcel.2019.06.030. Epub 2019 Jul 31.


Cotranslational processing of newly synthesized proteins is fundamental for correct protein maturation. Protein biogenesis factors are thought to bind nascent polypeptides not before they exit the ribosomal tunnel. Here, we identify a nascent chain recognition mechanism deep inside the ribosomal tunnel by an essential eukaryotic cytosolic chaperone. The nascent polypeptide-associated complex (NAC) inserts the N-terminal tail of its β subunit (N-βNAC) into the ribosomal tunnel to sense substrates directly upon synthesis close to the peptidyl-transferase center. N-βNAC escorts the growing polypeptide to the cytosol and relocates to an alternate binding site on the ribosomal surface. Using C. elegans as an in vivo model, we demonstrate that the tunnel-probing activity of NAC is essential for organismal viability and critical to regulate endoplasmic reticulum (ER) protein transport by controlling ribosome-Sec61 translocon interactions. Thus, eukaryotic protein maturation relies on the early sampling of nascent chains inside the ribosomal tunnel.

Keywords: ER targeting; NAC; RAC; SRP; Sec61; chaperone; nascent chain; nascent polypeptide-associated complex; protein biogenesis; ribosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / biosynthesis*
  • Caenorhabditis elegans Proteins / genetics
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Protein Biosynthesis*
  • Ribosomes / genetics
  • Ribosomes / metabolism*
  • SEC Translocation Channels / genetics
  • SEC Translocation Channels / metabolism*
  • Saccharomyces cerevisiae


  • Caenorhabditis elegans Proteins
  • SEC Translocation Channels