The molecular mechanism of cotranslational membrane protein recognition and targeting by SecA

Nat Struct Mol Biol. 2019 Oct;26(10):919-929. doi: 10.1038/s41594-019-0297-8. Epub 2019 Sep 30.


Cotranslational protein targeting is a conserved process for membrane protein biogenesis. In Escherichia coli, the essential ATPase SecA was found to cotranslationally target a subset of nascent membrane proteins to the SecYEG translocase at the plasma membrane. The molecular mechanism of this pathway remains unclear. Here we use biochemical and cryoelectron microscopy analyses to show that the amino-terminal amphipathic helix of SecA and the ribosomal protein uL23 form a composite binding site for the transmembrane domain (TMD) on the nascent protein. This binding mode further enables recognition of charged residues flanking the nascent TMD and thus explains the specificity of SecA recognition. Finally, we show that membrane-embedded SecYEG promotes handover of the translating ribosome from SecA to the translocase via a concerted mechanism. Our work provides a molecular description of the SecA-mediated cotranslational targeting pathway and demonstrates an unprecedented role of the ribosome in shielding nascent TMDs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • Escherichia coli K12 / chemistry
  • Escherichia coli K12 / metabolism*
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism*
  • Models, Molecular
  • Protein Biosynthesis
  • Protein Domains
  • Protein Structure, Secondary
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / metabolism*
  • SEC Translocation Channels / chemistry
  • SEC Translocation Channels / metabolism
  • SecA Proteins / chemistry
  • SecA Proteins / metabolism*


  • Escherichia coli Proteins
  • Ribosomal Proteins
  • SEC Translocation Channels
  • SecA protein, E coli
  • SecA Proteins