Membrane Insertion of Tail‐anchored Proteins

Abstract

Tail‐anchored proteins are a special class of transmembrane proteins, consisting of a cytosolic domain anchored to the phospholipid bilayer by a single hydrophobic segment adjacent to their most C‐terminus. Because of their particular topology, the C‐terminal anchor must be inserted into membranes post‐translationally by mechanisms that differ from the well‐known targeting/translocation co‐translational pathway. Recently, several advances have created a new understanding of the tail‐anchored protein insertion machinery. Because of the essential cellular roles carried out by tail‐anchored proteins, including vesicle fusion, regulation of apoptosis and formation of interorganellar contact sites, uncovering the machinery responsible for their biogenesis should further our ability to understand a wide variety of diseases such as forms of cancer caused by activation of the tail‐anchored protein oncogene BCL2.

Key Concepts

  • Tail‐anchored proteins have C‐terminal hydrophobic domains.
  • Tail‐anchored proteins are inserted post‐translationally into the membrane.
  • The GET complex inserts tail‐anchored proteins into the endoplasmic reticulum membrane in yeast.
  • The TRC complex chaperones tail‐anchored proteins into endoplasmic reticulum membranes in mammals.
  • The mitochondrial outer membrane appears to be the preferred destination of tail‐anchored proteins that fail to engage the GET/TRC complex.
  • Functions of the GET/TRC pathway additional to tail‐anchored protein targeting are presently under intense investigation.

Keywords: tail‐anchored proteins; membrane insertion; GET/TRC; ATPase; endoplasmic reticulum; mitochondria

Figure 1. Topology of TAMPs. (a) Compares the topology of TAMPs with that of other single‐spanning and of polytopic transmembrane proteins. (b) Shows how the tail anchor (red) of TAMPs (right), unlike the signal anchor (red) of classical type II proteins (left), is unable to interact co‐translationally with signal recognition particle (brown).
Figure 2. Biogenetic pathways of TA proteins. After release from ribosomes, a TA protein (red) can insert into the ER (1), the OMM (2) or the peroxisomal membrane (3) (and into the chloroplast outer envelope in plant cells, not depicted here). TA proteins may also reach the peroxisomal membrane by targeting first to specialised ER subdomains (4), followed by maturation of these domains into the mature organelle (foot prints). Localisation to the thicker, cholesterol‐containing membranes that delimit downstream compartments of the exo–endocytic pathway is attained by vesicular transport from the ER (paw marks). Reproduced from Borgese et al. (2007). © Elsevier.
Figure 3. Completely closed and open states of Get3 dimer. (a, b) The open (nucleotide‐free) and closed (ADP‐AlF4‐bound) state, respectively. Hydrophobic residues are coloured green; positively and negatively charged residues are in blue and red, respectively. The dimensions of the composite hydrophobic groove are indicated on the right side of (b). Reproduced from Mateja et al. (2009). © Nature Publishing Group.
Figure 4. Schematic representation of the TAMP insertion cycle in yeast, as described in the text. Free TAMP, indicated at step 2, most probably is never present, as the TAMP is likely captured by chaperones immediately after release from the ribosome, for subsequent delivery to Sgt2. The ATP‐ and ADP‐bound states of Get3 are indicated as D and T, respectively. The TMD of the TAMP substrate is shown in red.
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Further Reading

Blobel G (2000) Protein targeting (Nobel lecture). Chemistry and Biochemistry 1: 86–102.

Borgese N, Colombo S and Pedrazzini E (2003) The tale of tail‐anchored proteins: coming from the cytosol and looking for a membrane. Journal of Cell Biology 161: 1013–1019.

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Hegde RS and Keenan RJ (2011) Tail‐anchored membrane protein insertion into the endoplasmic reticulum. Nature Reviews in Molecular Cell Biology 12: 787–798.

Neupert W (1997) Protein import into mitochondria. Annual Reviews in Biochemistry 66: 863–917.

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Shao S and Hegde RS (2011) Membrane protein insertion at the endoplasmic reticulum. Annual Reviews in Cell and Developmental Biology 27: 25–56.

Smith JJ and Aitchison JD (2013) Peroxisomes take shape. Nature Reviews in Molecular Cell Biology 14: 803–817.

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Borgese, Nica(Feb 2015) Membrane Insertion of Tail‐anchored Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021876.pub2]