Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (Homo sapiens)

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3, 4, 6-8, 10...2, 6, 11, 17, 23...3, 10, 15, 24, 25, 29...2, 6, 8, 11, 17...15, 20, 29, 30, 3515, 16, 19-22, 37...1, 10, 15, 25, 3510, 15, 19, 22, 25endoplasmic reticulum membranecytosolCYB5A-1 ATP APP-C99 OTOF UBE2J2-1 STX5 ADP CYB5A-1 VAMP2 STX1A CAMLG UBL4A VAMP2 VAMP2 ASNA1 VAPA VAMP2 ALDH3A2-1 OTOF HMOX1 SERP1 ASNA1 HMOX1 Tail-anchoredproteinsSGTA STX5 WRB PRNP EMD HMOX1 BAG6:GET4:UBL4ATail-anchoredprotein:SGTA dimerSERP1 UBL4A EMD SGTA dimerUBE2J2-1 ASNA1 VAMP2 SEC61B PiEMD ASNA1 VAPA STX1A OTOF APP-C99 SERP1 SEC61G UBL4A BAG6 ALDH3A2-1 GET4 SEC61B UBE2J2-1 SERP1 APP-C99 STX5 WRB:CAMLGCYB5A-1 ASNA1 Mislocalizedmembraneprotein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPSTX5 VAPA ALDH3A2-1 UBE2J2-1 VAPA ASNA1:ATP dimerVAPA Tail-anchoredproteinsSTX5 BAG6 VAMP2 PRNP CYB5A-1 CYB5A-1 WRB SEC61B HMOX1 SEC61G ALDH3A2-1 ATP HMOX1 UBE2J2-1 STX1A ASNA1 SGTA SGTA CYB5A-1 STX1A SEC61G ADPEMD Tail-anchoredprotein:ASNA1:ADPTail-anchoredprotein:ASNA1:ATPVAMP2 OTOF STX1A ALDH3A2-1 SEC61B SERP1 Tail-anchoredprotein:ASNA1:ADP:WRB:CAMLGEMD GET4 STX5 VAMP2 SEC61G BAG6 VAMP2 STX1A Mislocalizedmembraneprotein:SGTA dimerVAPA SERP1 SEC61B HMOX1 ATP OTOF ATP SEC61G SEC61G ADP SEC61B SERP1 Mislocalizedmembrane proteinGET4 PRNP CAMLG VAPA OTOF UBE2J2-1 HMOX1 STX1A Tail-anchoredprotein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPSEC61G SGTA UBE2J2-1 SEC61B CYB5A-1 ALDH3A2-1 EMD ATPSTX5 SGTA OTOF EMD ALDH3A2-1 VAMP2 153023, 261015, 19, 20105, 20159101, 1823, 26


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.

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Reactome-Converter 
Pathway is converted from Reactome ID: 9609523
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Reactome version: 75
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

CompareRevisionActionTimeUserComment
115068view17:01, 25 January 2021ReactomeTeamReactome version 75
113512view11:59, 2 November 2020ReactomeTeamReactome version 74
112834view18:40, 9 October 2020DeSlOntology Term : 'protein secretory pathway' added !
112779view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADP MetaboliteCHEBI:456216 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
ALDH3A2-1 ProteinP51648-1 (Uniprot-TrEMBL)
APP-C99 ProteinP05067 (Uniprot-TrEMBL)
ASNA1 ProteinO43681 (Uniprot-TrEMBL)
ASNA1:ATP dimerComplexR-HSA-9609895 (Reactome)
ATP MetaboliteCHEBI:30616 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
BAG6 ProteinP46379 (Uniprot-TrEMBL)
BAG6:GET4:UBL4AComplexR-HSA-9609902 (Reactome)
CAMLG ProteinP49069 (Uniprot-TrEMBL)
CYB5A-1 ProteinP00167-1 (Uniprot-TrEMBL)
EMD ProteinP50402 (Uniprot-TrEMBL)
GET4 ProteinQ7L5D6 (Uniprot-TrEMBL)
HMOX1 ProteinP09601 (Uniprot-TrEMBL)
Mislocalized

membrane

protein:SGTA dimer
ComplexR-HSA-9617602 (Reactome)
Mislocalized

membrane

protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATP
ComplexR-HSA-9617598 (Reactome)
Mislocalized membrane proteinComplexR-HSA-9617594 (Reactome)
OTOF ProteinQ9HC10 (Uniprot-TrEMBL)
PRNP ProteinP04156 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
SEC61B ProteinP60468 (Uniprot-TrEMBL)
SEC61G ProteinP60059 (Uniprot-TrEMBL)
SERP1 ProteinQ9Y6X1 (Uniprot-TrEMBL)
SGTA ProteinO43765 (Uniprot-TrEMBL)
SGTA dimerComplexR-HSA-9610464 (Reactome)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX5 ProteinQ13190 (Uniprot-TrEMBL)
Tail-anchored protein:ASNA1:ADP:WRB:CAMLGComplexR-HSA-9609912 (Reactome)
Tail-anchored protein:ASNA1:ADPComplexR-HSA-9628396 (Reactome)
Tail-anchored protein:ASNA1:ATPComplexR-HSA-9609923 (Reactome)
Tail-anchored protein:SGTA dimerComplexR-HSA-9610465 (Reactome)
Tail-anchored protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPComplexR-HSA-9610487 (Reactome)
Tail-anchored proteinsComplexR-HSA-9609893 (Reactome)
Tail-anchored proteinsComplexR-HSA-9609909 (Reactome)
UBE2J2-1 ProteinQ8N2K1-1 (Uniprot-TrEMBL)
UBL4A ProteinP11441 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAPA ProteinQ9P0L0 (Uniprot-TrEMBL)
WRB ProteinO00258 (Uniprot-TrEMBL)
WRB:CAMLGComplexR-HSA-9609864 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9609917 (Reactome)
ASNA1:ATP dimerArrowR-HSA-9609917 (Reactome)
ASNA1:ATP dimerR-HSA-9610442 (Reactome)
ASNA1:ATP dimerR-HSA-9617596 (Reactome)
ATPR-HSA-9609917 (Reactome)
BAG6:GET4:UBL4AArrowR-HSA-9609860 (Reactome)
BAG6:GET4:UBL4AR-HSA-9610442 (Reactome)
BAG6:GET4:UBL4AR-HSA-9617596 (Reactome)
Mislocalized

membrane

protein:SGTA dimer
ArrowR-HSA-9617595 (Reactome)
Mislocalized

membrane

protein:SGTA dimer
R-HSA-9617596 (Reactome)
Mislocalized

membrane

protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATP
ArrowR-HSA-9617596 (Reactome)
Mislocalized membrane proteinR-HSA-9617595 (Reactome)
PiArrowR-HSA-9609860 (Reactome)
R-HSA-9609860 (Reactome) A properly folded tail-anchored (TA) protein is transferred from SGTA to ASNA1 via the BAG6 complex (BAG6:UBL4A:GET4 also known at BAT3:GET5:TRC35) (Marriapan et al. 2010, Leznicki et al. 2011, Mock et al. 2015, Shao et al. 2017, Guna et al. 2018). The TA protein bound to ASNA1 is then presumed to dissociate from the BAG6 complex (inferred from yeast homologs). At some point during or shortly after dissociation, ASNA1 hydrolyzes bound ATP to yield ADP (inferred from yeast homologs).
Improperly 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).
R-HSA-9609899 (Reactome) A tail-anchored protein bound to ASNA1 dimer (TRC40 dimer) in the cytosol (Stefanovic and Hegde 2007, Favaloro et al. 2008, Favaloro et al. 2010) docks at the WRB:CAMLG complex located in the endoplasmic reticulum membrane (Vilardi et al. 2011, Yamamoto and Sakisaka 2012, Vilardi et al. 2014, Colombo et al. 2016, Pfaff et al. 2016, Vogl et al. 2016). The cytoplasmic coiled coil domain of WRB and the cytoplasmic N-terminal domain of CAMLG compete for binding to ASNA1 (Vilardi et al. 2011, Yamamoto and Sakisaka 2012). As inferred from yeast homologs, ASNA1 hydrolyzes bound ATP at some point, resulting in a change of conformation of ASNA1. This may transfer the tail-anchored protein to WRB:CAMLG, which functions as an insertase.
R-HSA-9609917 (Reactome) A tail-anchored protein bound to ASNA1 (TRC40) (Stefanovic and Hegde 2007, Favaloro et al. 2008, Favaloro et al. 2010) docked at the WRB:CAMLG complex (also known as the WRB:CAML complex) located in the endoplasmic reticulum membrane is released into the ER membrane in an incompletely characterized reaction (Vilardi et al. 2011, Yamamoto and Sakisaka 2012, Vilardi et al. 2014, Colombo et al. 2016, Pfaff et al. 2016, Vogl et al. 2016). Experiments with yeast homologs (GET1 is the homologue of WRB and GET2 is the homologue of CAMLG) indicate that docking of ASNA1:ADP with WRB:CAMLG results in a conformational change in ASNA1 that causes release of the tail-anchored protein to WRB:CAMLG and then into the membrane (inferred from yeast homologs), ADP dissociates from ASNA1 at some point during the reaction. Exchange of ADP for ATP by ASNA1 then recycles ASNA1 back into the cytosol (inferred from yeast homologs).
R-HSA-9609921 (Reactome) The C-terminal domains of a SGTA dimer bind the C-terminal hydrophobic transmembrane domain (TMD) of a tail-anchored (TA) protein shortly after it emerges from the ribosome (Liou and Wang 2005, Leznicki et al. 2011, Wunderley et al. 2014, Shao et al. 2017). Binding of SGTA shields the TMD of the TA protein and stabilizes the TA protein by preventing it from being targeted for degradation (Leznicki and High 2012).
R-HSA-9610442 (Reactome) A SGTA dimer bound to a tail-anchored (TA) protein 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, Darby et al. 2014, Kuwabara et al. 2015, Mock et al. 2015, Shao et al. 2017, also inferred from rabbit homologs in Mariappan et al. 2010). At some point, ASNA1 (TRC40) also binds the complex (Shao et al. 2017). SGTA interacts with the ubiquitin-like domain (UBL) of BAG6 and the UBL of UBL4A competes with BAG6 for binding to SGTA (Chartron et al. 2012, Xu et al. 2012, Leznicki et al. 2013, Darby et al. 2014, Shao et al. 2017).
R-HSA-9617595 (Reactome) Membrane proteins are not delivered to membranes with complete efficiency and a portion can end up mislocalized to the cytosol. SGTA binds the hydrophobic regions of such mislocalized proteins that are exposed to the cytosol (Leznicki and High 2012, Xu et al. 2012, Wunderly et al. 2014, Shao et al. 2017). Client proteins of SGTA include both tail-anchored proteins destined for insertion into the endoplasmic reticulum membrane (Leznicki et al. 2013) and inappropriately localized proteins such as cytosolic PRNP (PrP) (Leznicki and High 2012), which is normally located in the plasma membrane. Mislocalized proteins bound by SGTA can be routed to the proteasome via ubiquitination by the BAG6 complex (BAG6:GET4:UBL4A) (Shao et al. 2017).
R-HSA-9617596 (Reactome) SGTA is believed to initially bind exposed hydrophobic regions of proteins (client proteins) in the cytosol and then associate with the BAG6 complex (BAG6:GET4:UBL4A) and ASNA1 (Mariappan et al. 2010, Hessa et al. 2011, Leznicki et al. 2012, Wunderly et al. 2014, Shao et al. 2017). If the client protein is not efficiently transferred to ASNA1 then the client protein is transferred to BAG6 (Shao et al. 2017), which has been demonstrated to bind hydrophobic regions of proteins and appears to prevent their aggregation prior to proteasomal degradation (Wang et al. 2011). The efficiency of transfer of a client protein to ASNA1 appears to be determined by the sequence of the hydrophobic domain (Hessa et al. 2011). SGTA is not a stable component of the BAG6 complex (Marriapan et al. 2010) and SGTA and RNF126 compete for the same binding site on BAG6 (Krysztofinska et al. 2016).
SGTA dimerArrowR-HSA-9609860 (Reactome)
SGTA dimerR-HSA-9609921 (Reactome)
SGTA dimerR-HSA-9617595 (Reactome)
Tail-anchored protein:ASNA1:ADP:WRB:CAMLGArrowR-HSA-9609899 (Reactome)
Tail-anchored protein:ASNA1:ADP:WRB:CAMLGR-HSA-9609917 (Reactome)
Tail-anchored protein:ASNA1:ADPArrowR-HSA-9609860 (Reactome)
Tail-anchored protein:ASNA1:ADPR-HSA-9609899 (Reactome)
Tail-anchored protein:ASNA1:ATPmim-catalysisR-HSA-9609860 (Reactome)
Tail-anchored protein:SGTA dimerArrowR-HSA-9609921 (Reactome)
Tail-anchored protein:SGTA dimerR-HSA-9610442 (Reactome)
Tail-anchored protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPArrowR-HSA-9610442 (Reactome)
Tail-anchored protein:SGTA:BAG6:GET4:UBL4A:ASNA1:ATPR-HSA-9609860 (Reactome)
Tail-anchored proteinsArrowR-HSA-9609917 (Reactome)
Tail-anchored proteinsR-HSA-9609921 (Reactome)
WRB:CAMLGArrowR-HSA-9609917 (Reactome)
WRB:CAMLGR-HSA-9609899 (Reactome)
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