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Mammalian ER retrotranslocon. The Grp170 protein plays a role during ERAD, positioning this client-release factor at the retrotranslocation site, allowing a mechanism to couple client release from BiP and retrotranslocation (Inoue and Tsai, 2016).

ER retrotranslocon of Homo sapiens
(1) p97 ATPase (valosin-containing protein, VCP) (P55072)
(2) Derlin-1 (NP_077271)
(3) VIMP (AAT46592)
(4) Ufd1 (Q541A5)
(5) Npl4 (Q8TAT6)
(6) gpUS11 (glycoprotein precursor) of HCMV (Q8UZK5)

ER retrotranslocon for misfolded luminal ER proteins.  Uses the ERAD-associated E3 ubiquitin-protein ligase, Hrd1p, which promotes polypeptide movement through the ER membrane (Carvalho et al., 2010; Bolte et al., 2011). As determined by cryoEM, Hrd1 is an 8 TMS dimer that associates with Hrd3 on the luminal side of the ER membrane to seal the channel used for protein retrotranslocation (Schoebel et al., 2017). The protein-conducting channel, Hrd1, is a ubiquitin ligase that serves as the transmembrane channel (Wu and Rapoport, 2018). The Cdc48/p97 ATPase pulls the unfolded substrate through the channel, out of the membrane. Cdc48 has a central pore, and the substrate protein passes from the cis side to the trans side (Wu and Rapoport, 2018). Otu1, ubiquitin thio ligase, partially de-ubiquitinates the substrate protein. The E3 ubiquitin-protein ligase accepts ubiquitin specifically from endoplasmic reticulum-associated UBC6 and UBC7 E2 ligases, and transfers it to substrates, promoting their degradation. It mediates the degradation of a broad range of substrates, including endoplasmic reticulum membrane proteins, soluble nuclear proteins and soluble cytoplasmic proteins. The DOA10 ubiquitin ligase complex is part of the ERAD-C pathway responsible for the rapid degradation of membrane proteins with misfolded cytoplasmic domains (Ravid et al., 2006). The 3-D structure of the Hrd1 complex (including Hrd1, Hrd3, Der1, Usa1 and Yos9) has been solved (Wu et al. 2020). It mediates the retrotranslocation of the polypeptide into the cytosol, which it is polyubiqutinated, extracted from the membrane by the Cdc48 ATPase complex and degraded by a proteosome.


ER retrotranslocon of Saccharomyces cerevisiae
(1) Cdc48 ATPase (NP_010157)
(2) Der1 (NP_009760)
(3) Npl4 (P33755)
(4) Hrd1p (ERAD-associated E2 ubiquitin-protein ligase) (5-6 N-terminal TMSs) (Q08109)
(5) 2TMS Hrd3p (Q05787)
(6) 3TMS Usa1p (E7KSD5) 
(7) Uba1 (E7LWL7)
(8) Ubc1 (E7Q288)
(9) Ubc6 (E7NGV2)
(10) Ubc7 (C8ZEM9)
(11) Ufd1 (C8Z8U3)
(12) DOA10 (P40318)
(13) OTU1 (P43558
(14) OS-9 homolog (Q99220)
(15) Deerlin 1-like protein, Dfm1, rhomboid-like protein (Q12743).

ERAD system in the endoplasmic reticulum of the malaria parasite, Plasmodium falciparum (Spork et al. 2009)

The ERAD system of Plasmodium falciparum 
Cdc48 (828aas) (C6KT34)
Der1-1 (212aas) (C7SP48)
Der1-2 (263aas) (Q8IJ82)
Hrd1 (510aas) (Q8ILM8)
Hrd3 (807aas) (O77341)
Nlp4 (531aas) (Q81426)
Ub (381aas) (Q7KQK2)
Uba1 (1,140aas) (Q815F9)
Uba2 (688aas) (Q81553)
Ubc (147aas) (Q81607)
Ufd1 (282aas) (Q8ILR6) 

ERAD-L retrotranslocon system. SEL1L-dependent substrates require Derlin2/3 and Herp1/2 regardless of their soluble or transmembrane nature. The ERAD-L substrates take several routes to the cytosol. The HRD1-engaged route 1 requires SEL1L, Derlin2 or Derlin3, and Herp1 or Herp2 (Sugimoto et al. 2017). The nucleotide exchange factor, Grp170, a homolog of HSP70 proteins, plays a role in this ERAD pathway (Inoue and Tsai 2016).

ERAD-L of Homo sapiens
HRD1 (E3) - SYVN1 of 617 aas and 6 N-terminal TMSs (Q86TM6)
gp87 (E3) - G-protein coupled receptor 87, GPR87; GPR95 of 358 aas and 7 TMSs (Q9BY21)
SEL1L - protein Sel-1 homolog, a partner of HRD1 of 794 aas and 3 TMSs, 1 N-terminal and 2 C-terminal (Q9UBV2)
Grp170 - homologous to heat shock proteins, Hsp70 (TC# 1.A.33) (Q9Y4L1)
Derlin 2 (DRL2) of 239 aas and 4 - 5 TMSs (Q9GZP9)
Derlin 3 (DRL3) of 235 aas and 5 TMSs (Q96Q80)
HERP 1, 337 aas with a C-terminal hydrophobic region that could be transmembrane (Q9UBP5)
HERP 2, 304 aas with a C-terminal hydrophobic region that could be transmembrane (Q9Y5J3)

The ER-associated degradation (ERAD) pathway of 47 proteins (Liu and Li 2014).

ERAD of Arabidopsis thaliana