Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (Homo sapiens)
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Description
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). View original pathway at Reactome.
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). View original pathway at Reactome.
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membrane
protein:SGTA dimermembrane
protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPAnnotated Interactions
membrane
protein:SGTA dimermembrane
protein:SGTA dimermembrane
protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPImproperly folded proteins and improperly localized hydrophobic proteins are transferred from SGTA to BAG6 rather than to ASNA1 (Shao et al. 2017). BAG6 then recruits RNF126 and facilitates the ubiquitination and consequent degradation of the defective protein. The selection of transferring a substrate protein from SGTA to ASNA1 or to BAG6 thereby acts as a "molecular triage". Proteins with less hydrophobic tail-anchors appear to be inserted into the endoplasmic reticulum membrane by a separate system comprising calmodulin and the ER membrane protein complex (Guna et al. 2018).