A Luminal Surveillance Complex that Selects Misfolded Glycoproteins for ER-Associated Degradation

• Published in: Cell Vol. 126; no. 2; pp. 349 - 359
• Main Authors: Denic, Vladimir, Quan, Erin M., Weissman, Jonathan S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-07-2006
• Subjects: Amino Acid Sequence; Binding Sites; Carboxypeptidases - genetics; Carboxypeptidases - metabolism; Carrier Proteins - metabolism; Cell Membrane - metabolism; Cytosol - metabolism; Endoplasmic Reticulum - metabolism; Fungal Proteins - metabolism; Glycoproteins - chemistry; Glycoproteins - metabolism; Glycosylation; HSP70 Heat-Shock Proteins - metabolism; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Models, Biological; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Substrate Specificity; Temperature; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2006.05.045

How the ER-associated degradation (ERAD) machinery accurately identifies terminally misfolded proteins is poorly understood. For luminal ERAD substrates, this recognition depends on their folding and glycosylation status as well as on the conserved ER lectin Yos9p. Here we show that Yos9p is part of a stable complex that organizes key components of ERAD machinery on both sides of the ER membrane, including the transmembrane ubiquitin ligase Hrd1p. We further demonstrate that Yos9p, together with Kar2p and Hrd3p, forms a luminal surveillance complex that both recruits nonnative proteins to the core ERAD machinery and assists a distinct sugar-dependent step necessary to commit substrates for degradation. When Hrd1p is uncoupled from the Yos9p surveillance complex, degradation can occur independently of the requirement for glycosylation. Thus, Yos9p/Kar2p/Hrd3p acts as a gatekeeper, ensuring correct identification of terminally misfolded proteins by recruiting misfolded forms to the ERAD machinery, contributing to the interrogation of substrate sugar status, and preventing glycosylation-independent degradation.