Tail-anchored membrane protein insertion into the endoplasmic reticulum

• Published in: Nature reviews. Molecular cell biology Vol. 12; no. 12; pp. 787 - 798
• Main Authors: Hegde, Ramanujan S., Keenan, Robert J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2011; Nature Publishing Group
• Subjects: 631/45/535; 631/80/313/1463; Animals; Biochemistry; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Humans; Life Sciences; Lipids; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membranes; Models, Biological; Molecular biology; Molecular chaperones; Physiological aspects; Polypeptides; Protein Biosynthesis; Proteins; review-article; Ribonucleic acid; Ribosomes - metabolism; RNA; Stem Cells; Substrate Specificity; United Kingdom
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm3226

Key Points
Tail-anchored (TA) proteins are a diverse and functionally important class of membrane proteins that are targeted to the endoplasmic reticulum (ER) by a newly discovered post-translational Get (guided entry of TA proteins) and transmembrane domain (TMD)-recognition complex (TRC) pathway.
TRC protein of 40 kDa (TRC40; Get3 in yeast) is an evolutionarily conserved ATPase that binds the hydrophobic TMD of a TA protein during targeting to the ER; TMD binding is mediated by a large hydrophobic groove in the ATP-bound, closed conformation of TRC40 or Get3.
TA proteins are first captured at the ribosome by a multi-component pre-targeting complex, which sorts cargo for targeting to the ER (via TRC40 or Get3), the mitochondrial outer membrane (via an unknown pathway) or the proteasome (for degradation).
In yeast, the Get3–TA substrate complex is recruited to the ER membrane by Get2 and then transferred to Get1 in an ATPase-dependent reaction that opens Get3 to drive substrate release.
After TA substrate release, ATP re-binding dissociates Get3 from Get1 and recycles it to the cytosol.
The characterization of the Get pathway, which directs the post-translational insertion of tail-anchored proteins into the membrane of the endoplasmic reticulum (ER), has been driven forward by structural studies and has revealed important parallels and distinctions with the classic co-translational pathway for ER membrane protein insertion.
Membrane proteins are inserted into the endoplasmic reticulum (ER) by two highly conserved parallel pathways. The well-studied co-translational pathway uses signal recognition particle (SRP) and its receptor for targeting and the SEC61 translocon for membrane integration. A recently discovered post-translational pathway uses an entirely different set of factors involving transmembrane domain (TMD)-selective cytosolic chaperones and an accompanying receptor at the ER. Elucidation of the structural and mechanistic basis of this post-translational membrane protein insertion pathway highlights general principles shared between the two pathways and key distinctions unique to each.