The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway.
To eliminate misfolded proteins that accumulate in the endoplasmic reticulum (ER) the cell mainly relies on ubiquitin-proteasome dependent ER-associated protein degradation (ERAD). Proteolysis of ERAD substrates by the proteasome requires their ubiquitylation and retro-translocation from the ER to the cytoplasm. Here we describe a high molecular mass protein complex associated with the ER membrane, which facilitates ERAD. It contains the ubiquitin domain protein (UDP) HERP, the ubiquitin protein ligase HRD1, as well as the retro-translocation factors p97, Derlin-1 and VIMP. Our data on the structural arrangement of these ERAD proteins suggest that p97 interacts directly with membrane-resident components of the complex including Derlin-1 and HRD1, while HERP binds directly to HRD1. We propose that ubiquitylation, as well as retro-translocation of proteins from the ER are performed by this modular protein complex, which permits the close coordination of these consecutive steps within ERAD.
Schulze
Andrea
A
Charité, Universitaetsmedizin Berlin, Campus Charité Mitte, Institut für Biochemie Monbijoustr. 2, 10117 Berlin, Germany.
Standera
Sybille
S
Buerger
Elke
E
Kikkert
Marjolein
M
van Voorden
Sjaak
S
Wiertz
Emmanuel
E
Koning
Frits
F
Kloetzel
Peter-Michael
PM
Seeger
Michael
M
D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D051140:Selenoproteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; C487709:DERL1 protein, human; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C487710:SELENOS protein, human; D051140:Selenoproteins; D025801:Ubiquitin; C094680:nuclear protein import factor p97; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein