Membrane Insertion of Tail‐anchored Proteins

Tail-anchored (TA) proteins are a special class of transmembrane proteins, which harbour only a single hydrophobic segment adjacent to their most C-terminus. This anchor must be inserted into membranes posttranslationally to allow for their correct cellular localization. Although TA proteins have essential cellular roles such as signal transduction, apoptosis and vesicle fusion, their biogenesis route has for many years remained unknown. Recently, several advances have created a new understanding of the TA protein insertion machinery. Uncovering the machinery responsible for the biogenesis of TA proteins should further our ability to understand a wide variety of diseases such as forms of cancer caused by activation of the TA protein oncogene BCL2.

Key concepts:

  • Tail-anchored proteins have C-terminal hydrophobic domains.
  • Tail-anchored proteins are inserted posttranslationally 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 membranes in humans.

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

Figure 1. Schematic representation of the insertion process for secretory pathway proteins containing transmembrane domains. Left shows the cotranslational translocation mechanism using signal sequence recognition particle and the translocon channel. On the right is a tail-anchored (TA) protein that requires posttranslational insertion.
Figure 2. Schematic representation of TA proteins and their possible cellular destinations. Once out of the ribosome, a TA protein can integrate either into the mitochondria or the ER from where it will continue to be distributed between membrane compartments connected by membrane contact sites or vesicular traffic.
Figure 3. Schematic representation of the TA protein insertion cycle in yeast. Letters refer to the different stages discussed in the text.
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 References
    Abell BM, Pool MR, Schlenker O, Sinning I and High S (2004) Signal recognition particle mediates post-translational targeting in eukaryotes. EMBO Journal 23: 2755–2764.
    Abell BM, Rabu C, Leznicki P, Young JC and High S (2007) Post-translational integration of tail-anchored proteins is facilitated by defined molecular chaperones. Journal of Cell Science 120: 1743–1751.
    Beilharz T, Egan B, Silver PA, Hofmann K and Lithgow T (2003) Bipartite signals mediate subcellular targeting of tail-anchored membrane proteins in Saccharomyces cerevisiae. Journal of Biological Chemistry 278: 8219–8223.
    Borgese N, Brambillasca S and Colombo S (2007) How tails guide tail-anchored proteins to their destinations. Current Opinion in Cell Biology 19: 368–375.
    Borgese N, Brambillasca S, Soffientini P, Yabal M and Makarow M (2003a) Biogenesis of tail-anchored proteins. Biochemical Society Transactions 31: 1238–1242.
    Borgese N, Colombo S and Pedrazzini E (2003b) The tale of tail-anchored proteins: coming from the cytosol and looking for a membrane. Journal of Cell Biology 161: 1013–1019.
    Borgese N, Gazzoni I, Barberi M, Colombo S and Pedrazzini E (2001) Targeting of a tail-anchored protein to endoplasmic reticulum and mitochondrial outer membrane by independent but competing pathways. Molecular Biology of the Cell 12: 2482–2496.
    Brambillasca S, Yabal M, Soffientini P et al. (2005) Transmembrane topogenesis of a tail-anchored protein is modulated by membrane lipid composition. EMBO Journal 24: 2533–2542.
    Bulbarelli A, Sprocati T, Barberi M, Pedrazzini E and Borgese N (2002) Trafficking of tail-anchored proteins: transport from the endoplasmic reticulum to the plasma membrane and sorting between surface domains in polarised epithelial cells. Journal of Cell Science 115: 1689–1702.
    Burri L and Lithgow T (2004) A complete set of SNAREs in yeast. Traffic 5: 45–52.
    Colombo SF, Longhi R and Borgese N (2009) The role of cytosolic proteins in the insertion of tail-anchored proteins into phospholipid bilayers. Journal of Cell Science 122: 2383–2392.
    Dimmer KS, Fritz S, Fuchs F et al. (2002) Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Molecular Biology of the Cell 13: 847–853.
    Egan B, Beilharz T, George R et al. (1999) Targeting of tail-anchored proteins to yeast mitochondria in vivo. FEBS Letters 451: 243–248.
    Egea PF, Stroud RM and Walter P (2005) Targeting proteins to membranes: structure of the signal recognition particle. Current Opinion in Structural Biology 15: 213–220.
    Favaloro V, Spasic M, Schwappach B and Dobberstein B (2008) Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins. Journal of Cell Science 121: 1832–1840.
    Fleischer TC, Weaver CM, McAfee KJ, Jennings JL and Link AJ (2006) Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes & Development 20: 1294–1307.
    Garcia PD, Hansen W and Walter P (1991) In vitro protein translocation across microsomal membranes of Saccharomyces cerevisiae. Methods in Enzymology 194: 675–682.
    Gorlich D and Rapoport TA (1993) Protein translocation into proteoliposomes reconstituted from purified components of the endoplasmic reticulum membrane. Cell 75: 615–630.
    Habib SJ, Vasiljev A, Neupert W and Rapaport D (2003) Multiple functions of tail-anchor domains of mitochondrial outer membrane proteins. FEBS Letters 555: 511–515.
    Hann BC and Walter P (1991) The signal recognition particle in S. cerevisiae. Cell 67: 131–144.
    Hu J, Li J, Qian X et al. (2009) Preliminary X-ray crystallographic studies of yeast Get3. Acta Crystallographica Section F: Structural Biology and Crystallization Communications 65: 489–491.
    Jonikas MC, Collins SR, Denic V et al. (2009) Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323: 1693–1697.
    Kalbfleisch T, Cambon A, Wattenberg BW et al. (2007) A bioinformatics approach to identifying tail-anchored proteins in the human genome. Traffic 8: 1687–1694.
    Kao G, Nordenson C, Still M et al. (2007) ASNA-1 positively regulates insulin secretion in C.elegans and mammalian cells. Cell 128: 577–587.
    Kemper C, Habib SJ, Engl G et al. (2008) Integration of tail-anchored proteins into the mitochondrial outer membrane does not require any known import components. Journal of Cell Science 121: 1990–1998.
    Krajewski S, Tanaka S, Takayama S et al. (1993) Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Research 53: 4701–4714.
    Kurdi-Haidar B, Hom DK, Flittner DE et al. (1998) Dual cytoplasmic and nuclear distribution of the novel arsenite-stimulated human ATPase (hASNA-I). Journal of Cellular Biochemistry 71: 1–10.
    Kutay U, Ahnert-Hilger G, Hartmann E, Wiedenmann B and Rapoport TA (1995) Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane. EMBO Journal 14: 217–223.
    Liou ST, Cheng MY and Wang C (2007) SGT2 and MDY2 interact with molecular chaperone YDJ1 in Saccharomyces cerevisiae. Cell Stress and Chaperones 12: 59–70.
    Lithgow T, van Driel R, Bertram JF and Strasser A (1994) The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth & Differentiation 5: 411–417.
    Mateja A, Szlachcic A, Downing ME et al. (2009) The structural basis of tail-anchored membrane protein recognition by Get3. Nature 461(7262): 361–366.
    Mukhopadhyay R, Ho YS, Swiatek PJ, Rosen BP and Bhattacharjee H (2006) Targeted disruption of the mouse Asna1 gene results in embryonic lethality. FEBS Letters 580: 3889–3894.
    Neupert W (1997) Protein import into mitochondria. Annual Review of Biochemistry 66: 863–917.
    Ogg SC, Poritz MA and Walter P (1992) Signal recognition particle receptor is important for cell growth and protein secretion in Saccharomyces cerevisiae. Molecular Biology of the Cell 3: 895–911.
    Pelham HR (1999) SNAREs and the secretory pathway-lessons from yeast. Experimental Cell Research 247: 1–8.
    Pfanner N and Meijer M (1997) The Tom and Tim machine. Current Biology 7: R100–R103.
    Prilusky J and Bibi E (2009) Studying membrane proteins through the eyes of the genetic code revealed a strong uracil bias in their coding mRNAs. Proceedings of the National Academy of Sciences of the USA 106: 6662–6666.
    Rabu C and High S (2007) Membrane protein chaperones: a new twist in the tail? Current Biology 17: R472–R474.
    Rabu C, Schmid V, Schwappach B and High S (2009) Biogenesis of tail-anchored proteins: the beginning for the end? Journal of Cell Science 122: 3605–3612. doi: 10.1242/jcs.041210.
    Rachubinski RA, Verma DP and Bergeron JJ (1980) Synthesis of rat liver microsomal cytochrome b5 by free ribosomes. Journal of Cell Biology 84: 705–716.
    Rapoport TA, Matlack KE, Plath K, Misselwitz B and Staeck O (1999) Posttranslational protein translocation across the membrane of the endoplasmic reticulum. Journal of Biological Chemistry 380: 1143–1150.
    Schnell DJ, Kessler F and Blobel G (1994) Isolation of components of the chloroplast protein import machinery. Science 266: 1007–1012.
    Schuldiner M, Collins SR, Thompson NJ et al. (2005) Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123: 507–519.
    Schuldiner M, Metz J, Schmid V et al. (2008) The GET complex mediates insertion of tail-anchored proteins into the ER membrane. Cell 134: 634–645.
    Shen J, Hsu CM, Kang BK, Rosen BP and Bhattacharjee H (2003) The Saccharomyces cerevisiae Arr4p is involved in metal and heat tolerance. Biometals 16: 369–378.
    Stefanovic S and Hegde RS (2007) Identification of a targeting factor for posttranslational membrane protein insertion into the ER. Cell 128: 1147–1159.
    Wattenberg B and Lithgow T (2001) Targeting of C-terminal (tail)-anchored proteins: understanding how cytoplasmic activities are anchored to intracellular membranes. Traffic 2: 66–71.
    Wickner W and Schekman R (2005) Protein translocation across biological membranes. Science 310: 1452–1456.
    Yabal M, Brambillasca S, Soffientini P et al. (2003) Translocation of the C terminus of a tail-anchored protein across the endoplasmic reticulum membrane in yeast mutants defective in signal peptide-driven translocation. Journal of Biological Chemistry 278: 3489–3496.
    Zimmer J, Nam Y and Rapoport TA (2008) Structure of a complex of the ATPase SecA and the protein-translocation channel. Nature 455: 936–943.
 Further Reading
    book Alberts B, Johnson A, Lewis J et al. (2007) Molecular Biology of the Cell, 5th edn. New York: Garland Science.
    book Lodish H, Berk A, Kaiser CA et al. (2007) Molecular Cell Biology, 6th edn. New York: Freeman.
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Schuldiner, Maya, Schwappach, Blanche, and Weissman, Jonathan S(Jan 2010) Membrane Insertion of Tail‐anchored Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021876]