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OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.

Nature cell biology | Mar 3, 2008

http://www.ncbi.nlm.nih.gov/pubmed/18264092

Terminally misfolded or unassembled proteins in the early secretory pathway are degraded by a ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD). How substrates of this pathway are recognized within the ER and delivered to the cytoplasmic ubiquitin-conjugating machinery is unknown. We report here that OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1. Both proteins contain conserved mannose 6-phosphate receptor homology (MRH) domains, which are required for interaction with SEL1L, but not with substrate. OS-9 associates with the ER chaperone GRP94 which, together with Hrd1 and SEL1L, is required for the degradation of an ERAD substrate, mutant alpha(1)-antitrypsin. These data suggest that XTP3-B and OS-9 are components of distinct, partially redundant, quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation in mammalian cells.

Pubmed ID: 18264092 RIS Download

Mesh terms: Endoplasmic Reticulum | Gene Expression Regulation | Humans | Lectins | Membrane Glycoproteins | Models, Biological | Mutation | Neoplasm Proteins | Protein Binding | Protein Denaturation | Protein Folding | Proteins | Receptor, IGF Type 2 | Ubiquitin | Ubiquitin-Protein Ligases | alpha 1-Antitrypsin

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM074874
  • Agency: NIGMS NIH HHS, Id: R01 GM074874-04

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