title: EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex.
abstract: Terminally misfolded or unassembled secretory proteins are retained in the endoplasmic reticulum (ER) and subsequently cleared by the ER-associated degradation (ERAD) pathway. The degradation of ERAD substrates involves mannose trimming of N-linked glycans; however, the mechanisms of substrate recognition and sorting to the ERAD pathway are poorly defined. EDEM1 (ER degradation-enhancing alpha-mannosidase-like 1 protein) has been proposed to play a role in ERAD substrate signaling or recognition. We show that EDEM1 specifically binds nonnative proteins in a glycan-independent manner. Inhibition of mannosidase activity with kifunensine or disruption of the EDEM1 mannosidase-like domain by mutation had no effect on EDEM1 substrate binding but diminished its association with the ER membrane adaptor protein SEL1L. These results support a model whereby EDEM1 binds nonnative proteins and uses its mannosidase-like domain to target aberrant proteins to the ER membrane dislocation and ubiquitination complex containing SEL1L.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Cormier
authors.forename: Taku
authors.initials: T
authors.lastname: Tamura
authors.forename: Johan C
authors.initials: JC
authors.lastname: Sunryd
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Hebert
mesh_terms: D001665:Binding Sites; D050260:Carbohydrate Metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008358:Mannose / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C486654:EDEM1 protein, human; D006023:Glycoproteins; D008565:Membrane Proteins; D011134:Polysaccharides; D011506:Proteins; C117384:SEL1L protein, human; D008358:Mannose