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Tail-anchored membrane protein insertion into the endoplasmic reticulum

Nature Reviews Molecular Cell Biology volume 12, pages 787798 (2011) | Download Citation

Abstract

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.

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.

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Acknowledgements

Research in the Hegde laboratory is supported by the Medical Research Council, UK. Research in the Keenan laboratory is supported by grants from the US National Institutes of Health (R01 GM086487), the Camille and Henry Dreyfus Foundation and the Edward Mallinckrodt, Jr Foundation. The authors thank members of their laboratories and other colleagues for helpful discussions.

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Affiliations

  1. Medical Research Council (MRC) Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK.

    • Ramanujan S. Hegde
  2. Department of Biochemistry and Molecular Biology, The University of Chicago, Gordon Center for Integrative Science, Room W238, Chicago, Illinois 60637, USA.

    • Robert J. Keenan

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ramanujan S. Hegde or Robert J. Keenan.

Glossary

Chaperones

A large group of proteins that facilitate the folding, assembly, transport and degradation of non-native polypeptides by minimizing inappropriate interactions.

Ribosomal exit tunnel

An internal channel in the large subunit of the ribosome through which the nascent polypeptide travels before emerging into the cytosol. Various factors bound to the ribosome surface can affect the folding and/or targeting of the nascent polypeptide as it emerges from the exit tunnel.

Translocon

A membrane channel that is associated with the transport of polypeptides into or across cellular membranes.

SNARE

(Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor). A family of tail-anchored coiled-coil proteins that regulate fusion reactions and target specificity in vesicle trafficking.

Heat shock protein 70

(HSP70). A ubiquitous family of 70 kDa heat-shock proteins that serve as molecular chaperones to regulate polypeptide folding, translocation and degradation.

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