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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). The cryo-EM structure of the ERAD protein channel, formed by tetrameric human Derlin-1, has been solved (Rao et al. 2021).  The structure shows that Derlin-1 forms a homotetramer that encircles a large tunnel traversing the ER membrane. The tunnel has a diameter of about 12 to 15 angstroms, large enough to allow an α-helix to pass through. The structure shows a lateral gate within the membrane, providing access of transmembrane proteins to the tunnel. Thus, Derlin-1 forms a protein channel for translocation of misfolded proteins. This structure is different from the monomeric yeast Derlin structure previously reported, which forms a semichannel with another protein (Rao et al. 2021).

Metazoa, Chordata
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. The importance of Hrd1 complex integrity during ERAD, suggests that allosteric interactions between transmembrane domains regulate Hrd1 complex formation (Nakatsukasa et al. 2022).


Fungi, Ascomycota
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).

Metazoa, Chordata
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).

Viridiplantae, Streptophyta
ERAD of Arabidopsis thaliana

The yeast multicomponent mitochondrial outer membrane-associated protein degradation (MOM-PD) pathway. Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins (quality control pathways). Metzger et al. 2020 established temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts-proteins Sen2-1HA(ts) (P16658; 329 aas, 0 TMSs) and Sam35-2HA(ts) (P14693; 329 aas and 1 TMS) are degraded using the MOM-PD pathway involving the ubiquitin-proteasome system. Ubiquitination of Sen2-1HA(ts) is mediated by the ubiquitin ligase (E3) Ubr1, while Sam35-2HA(ts) is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires the SSA family of Hsp70s (e.g., P10591; 642 aas and 0 TMSs) and the Hsp40 Sis1 (P25294; 352 aas and 0 TMSs), providing evidence for chaperone involvement in MOM-PD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex (see TC# 3.A.16.1.2), Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. Thus, a unique QC pathway consists of a combination of cytosolic and mitochondrial factors and distinguishes it from other cellular QC pathways (Metzger et al. 2020). Nevertheless, most of the protein constituents have homologs in TC family 3.A.16.

Fungi, Ascomycota
MOM-PD of Saccharomyces cerevisiae
In addition to the Cdc48-Npl4-Ufd1 complex (see 3.A.16.1.2), the other consituents are:
The SSA family Hsp70 protein, P10591 of 642 aas, 0 TMSs
The Hsp40 homolog, Sis1 (P25294; 352 aas, 0 TMSs
The Doa1 (UFD3, ZZZ4) protein (P36037; 715 aas, 0 TMSs)
The ubiquitin ligase, Ubr1, Ptr1 (P19812; 1950 aas and 0-2 TMSs)
The Cdc48 adaptor, Ubx2 or Sel1 (Q04228; 584 aas and possibly 3 TMSs in a 1 + 2 TMS arrangement)
The San1 protein (P22470; 610 aas and 0 TMSs)