Insertion of tail-anchored proteins into the endoplasmic reticulum membrane

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Homo sapiens
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Tail-anchored (TA) proteins have a hydrophobic transmembrane domain (TMD) located near the C-terminus ("tail") of the protein. Depending on the nature of the TMD, TA proteins can be inserted into the endoplasmic reticulum (ER) membrane by at least 4 mechanisms: cotranslational insertion by the signal recognition particle (SRP), post-translational insertion by ASNA1 (TRC40), post-translational insertion by the SRP, and post-translational insertion by a SRP-independent mechanism (SND) (Casson et al. 2017, reviewed in Borgese and Fasana 2011, Casson et al. 2016, Aviram et al. 2016, Chio et al. 2017). Much of the information about the mammalian system of insertion by ASNA1 (TRC40) has been inferred from the Saccharomyces cerevisiae homologue Get3.
Prior to post-translational insertion by ASNA1, SGTA binds the transmembrane domain of the substrate TA protein immediately after translation (Leznicki et al. 2011, Leznicki and High 2012, Xu et al. 2012, Wunderly et al. 2014, Shao et al. 2017), the SGTA:TA protein complex then binds the BAG6 complex (BAG6:GET4:UBL4A) via UBL4A (Winnefeld et al. 2006, Chartron et al. 2012, Xu et al. 2012, Leznicki et al. 2013, Mock et al. 2015, Kuwabara et al. 2015, Shao et al. 2017), and the TA protein is transferred to ASNA1 (Mariappan et al. 2010, Leznicki et al. 2011, Shao et al. 2017), also bound by the BAG6 complex via UBL4A. The ASNA1:TA protein complex then docks at the WRB:CAMLG (WRB:CAML) complex located in the ER membrane and the TA protein is inserted into the ER membrane by an uncharacterized mechanism that involves ATP and the transmembrane domain insertase activity of the WRB:CAML complex (Vilardi et al. 2011, Vilardi et al. 2014, Vogl et al. 2016, and inferred from yeast in Wang et al. 2014).
Misfolded TA proteins, overexpressed TA proteins, and membrane proteins mislocalized in the cytosol bind SGTA but are not efficiently transferred to ASNA1 and, instead, are retained by BAG6 which recruits RNF126 to ubiquitinate them, targeting them for degradation by the proteasome (Wang et al. 2011, Leznicki and High 2012, Xu et al. 2012, Rodrigo-Brenni et al. 2014, Wunderly et al. 2014, Shao et al. 2017, reviewed in Lee and Ye 2013, Casson et al. 2016, Krysztofinska et al. 2016, Guna and Hegde 2018).
Literature References
PubMed ID Title Journal Year
27193484 Structural and functional insights into the E3 ligase, RNF126

High, S, Evans, NJ, Isaacson, RL, Krysztofinska, EM, Martínez-Lumbreras, S, Thapaliya, A

Sci Rep 2016
21466504 A biochemical analysis of the constraints of tail-anchored protein biogenesis

High, S, Warwicker, J, Leznicki, P

Biochem. J. 2011
20646998 Targeting pathways of C-tail-anchored proteins

Fasana, E, Borgese, N

Biochim. Biophys. Acta 2011
25535373 Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain

Zaslaver, M, Chartron, JW, Mock, JY, Clemons, WM, Ye, Y, Xu, Y

Proc. Natl. Acad. Sci. U.S.A. 2015
25713138 Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis

Senda, T, Kawahara, H, Kuwabara, N, Matsumoto, H, Minami, R, Yokota, N, Kato, R

J. Biol. Chem. 2015
29021347 Multiple pathways facilitate the biogenesis of mammalian tail-anchored proteins

High, S, Zimmerman, R, Aviram, N, McKenna, M, Casson, J, Haßdenteufel, S

J. Cell. Sci. 2017
20676083 A ribosome-associating factor chaperones tail-anchored membrane proteins

Hegde, RS, Li, X, Sharma, A, Stefanovic, S, Keenan, RJ, Mariappan, M, Mateja, A

Nature 2010
23129660 SGTA antagonizes BAG6-mediated protein triage

High, S, Leznicki, P

Proc. Natl. Acad. Sci. U.S.A. 2012
21636303 A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation

Hegde, R, Soetandyo, N, Baek, K, Ye, Y, Liu, Y, Wang, Q

Mol. Cell 2011
28104892 Mechanistic basis for a molecular triage reaction

Hegde, RS, Shao, S, Kivlen, MH, Rodrigo-Brenni, MC

Science 2017
24981174 Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6

Gutierrez, E, Hegde, RS, Rodrigo-Brenni, MC

Mol. Cell 2014
25179605 SGTA regulates the cytosolic quality control of hydrophobic substrates

High, S, Payapilly, A, Leznicki, P, Wunderley, L

J. Cell. Sci. 2014
23533635 The association of BAG6 with SGTA and tail-anchored proteins

High, S, Warwicker, J, Schwappach, B, Isaacson, RL, Krysztofinska, EM, Leznicki, P, Clancy, A, Roebuck, QP, Wunderley, L

PLoS ONE 2013
23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation

Yang, Y, Ye, Y, Huang, L, Cai, M, Xu, Y

Cell Rep 2012
23142665 Structures of the Sgt2/SGTA dimerization domain with the Get5/UBL4A UBL domain reveal an interaction that forms a conserved dynamic interface

VanderVelde, DG, Clemons, WM, Chartron, JW

Cell Rep 2012
27458190 Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing

Strenzke, N, Kwan, KY, Yamanbaeva, G, Schwappach, B, Wichmann, C, del Castillo, I, Vilardi, F, Wu, X, Wojcik, SM, Rodriguez-Ballesteros, M, Lin, SY, Vogl, C, Panou, I, Cardenas, E, Santarelli, R, Moser, T, Weber, T, Jung, S, Indzhykulian, AA, Corey, DP, Mangosing, SJ, Pangršič, T

EMBO J. 2016
28992441 Mechanisms of Tail-Anchored Membrane Protein Targeting and Insertion

Cho, H, Shan, SO, Chio, US

Annu. Rev. Cell Dev. Biol. 2017
16777091 Human SGT interacts with Bag-6/Bat-3/Scythe and cells with reduced levels of either protein display persistence of few misaligned chromosomes and mitotic arrest

Spring, H, Cziepluch, C, Schnölzer, M, Winnefeld, M, Knoch, TA, Grewenig, A, Gan, EC, Rommelaere, J

Exp. Cell Res. 2006
21444755 WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane

Dobberstein, B, Lorenz, H, Vilardi, F

J. Cell. Sci. 2011
25043001 The Get1/2 transmembrane complex is an endoplasmic-reticulum membrane protein insertase

Weir, NR, Chan, C, Wang, F, Denic, V

Nature 2014
23417671 Bag6/Bat3/Scythe: a novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation

Lee, JG, Ye, Y

Bioessays 2013
24392163 WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane

Schwappach, B, Stephan, M, Vilardi, F, Janshoff, A, Clancy, A

PLoS ONE 2014
27905431 The SND proteins constitute an alternative targeting route to the endoplasmic reticulum

Jung, M, Aviram, N, Schwappach, B, Jan, CH, Schorr, S, Schuldiner, M, Costa, EA, Ast, T, Chuartzman, SG, Arakel, EC, Zimmermann, R, Weissman, JS, Dudek, J, Haßdenteufel, S

Nature 2016
27284044 On the road to nowhere: cross-talk between post-translational protein targeting and cytosolic quality control

High, S, McKenna, M, Casson, J

Biochem. Soc. Trans. 2016
29689233 Transmembrane Domain Recognition during Membrane Protein Biogenesis and Quality Control

Hegde, RS, Guna, A

Curr. Biol. 2018
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