Membrane protein insertion at the endoplasmic reticulum

Annu Rev Cell Dev Biol. 2011;27:25-56. doi: 10.1146/annurev-cellbio-092910-154125. Epub 2011 Jul 21.


Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to overcome these obstacles.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Intracellular Membranes / chemistry
  • Intracellular Membranes / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Protein Transport
  • SEC Translocation Channels
  • Signal Recognition Particle / chemistry
  • Signal Recognition Particle / metabolism


  • Guanine Nucleotide Exchange Factors
  • Membrane Proteins
  • SEC Translocation Channels
  • Signal Recognition Particle
  • Adenosine Triphosphatases