Figure 2.

Models of glycoprotein endoplasmic reticulum-associated degradation (ERAD). Various models of the delivery of ERAD substrates to an ER membrane ERAD complex are depicted. Letters A–D designate the different routes for a misfolded substrate. The glycan attached to an ERAD substrate (black sinuous line) is trimmed of a mannose residue by ER mannosidase I (ER Man I, step 1). This is followed by ER-degradation enhancing mannosidase-like protein (EDEM)1 recognition. EDEM1 is present in a complex with ERdj5 and immunoglobulin binding protein (BiP). In the mannose timer model, EDEM1 acts as a mannosidase to trim additional mannose residues (step 2). In route A, ERAD substrates are directly recognized by type I membrane glycoprotein (SEL1L) (step 3). OS-9 and XTP3-B associate with SEL1L to act as ERAD gatekeepers by querying the ERAD substrate for exposed α1,6-linked mannose residues. If the protein possesses the proper glycans, it is passed along the ERAD pathway (step 4). In route B, alternatively, trimmed ERAD substrates are recognized by OS-9 and XTP3-B (step 5) and delivered to the ERAD membrane complex (step 6). Routes C and D depict glycan docking models for OS-9–XTP3-B and EDEM1, respectively. In route C, OS-9 and XTP3-B recognize the misfolded substrates through protein–protein interactions (step 7). This can involve associated co-factors such as GRP94. OS-9 and XTP3-B then deliver the ERAD substrate to the ER membrane ERAD complex by binding to the glycans on the adapter SEL1L (step 8) or on a glycosylated SEL1L associated protein. In route D, the EDEM1 complex associates with ERAD substrates (step 9). EDEM1 employs its mannosidase-like domain to deliver the ERAD substrate to the ER membrane ERAD complex (step 10). The models depicted are not necessarily mutually exclusive. Hybrid models that use multiple pathways are possible. Note that although glycans trimmed to Man7–5 can signal for ERAD in metazoans, the Man6 composition is displayed for simplicity.