Modularity of the Hrd1 ERAD complex underlies its diverse client range.
Secretory protein folding is monitored by endoplasmic reticulum (ER) quality control mechanisms. Misfolded proteins are retained and targeted to ER-associated degradation (ERAD) pathways. At their core are E3 ubiquitin ligases, which organize factors that recognize, ubiquitinate, and translocate substrates. Of these, we report that the Hrd1 complex manages three distinct substrate classes. A core complex is required for all classes and is sufficient for some membrane proteins. The accessory factors Usa1p and Der1p adapt the complex to process luminal substrates. Their integration is sufficient to process molecules bearing glycan-independent degradation signals. The presence of Yos9p extends the substrate range by mediating the recognition of glycan-based degradation signals. This modular organization enables the Hrd1 complex to recognize topologically diverse substrates. The Hrd1 system does not directly evaluate the folding state of polypeptides. Instead, it does so indirectly, by recognizing specific embedded signals displayed upon misfolding.
Kanehara
Kazue
K
Temasek Life Sciences Laboratory, National University of Singapore, Singapore.
Xie
Wei
W
Ng
Davis T W
DT
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D017510:Protein Folding; D021382:Protein Sorting Signals / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C098515:DER1 protein, S cerevisiae; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011134:Polysaccharides; D021382:Protein Sorting Signals; D029701:Saccharomyces cerevisiae Proteins; C546121:Usa1 protein, S cerevisiae; C495027:Yos9 protein, S cerevisiae; C104621:HRD1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases