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J Biol Chem. 2014 Sep 12;289(37):25670-7. doi: 10.1074/jbc.M114.583344. Epub 2014 Aug 1.

Misfolded proteins induce aggregation of the lectin Yos9.

Author information

1
From the Department of Cellular and Molecular Pharmacology, Graduate Group in Biophysics, California Institute for Quantitative Biosciences, Center for RNA Systems Biology, and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94158.
2
From the Department of Cellular and Molecular Pharmacology, Graduate Group in Biophysics, California Institute for Quantitative Biosciences, Center for RNA Systems Biology, and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94158 Jonathan.Weissman@ucsf.edu.

Abstract

A substantial fraction of nascent proteins delivered into the endoplasmic reticulum (ER) never reach their native conformations. Eukaryotes use a series of complementary pathways to efficiently recognize and dispose of these terminally misfolded proteins. In this process, collectively termed ER-associated degradation (ERAD), misfolded proteins are retrotranslocated to the cytosol, polyubiquitinated, and degraded by the proteasome. Although there has been great progress in identifying ERAD components, how these factors accurately identify substrates remains poorly understood. The targeting of misfolded glycoproteins in the ER lumen for ERAD requires the lectin Yos9, which recognizes the glycan species found on terminally misfolded proteins. In a role that remains poorly characterized, Yos9 also binds the protein component of ERAD substrates. Here, we identified a 45-kDa domain of Yos9, consisting of residues 22-421, that is proteolytically stable, highly structured, and able to fully support ERAD in vivo. In vitro binding studies show that Yos9(22-421) exhibits sequence-specific recognition of linear peptides from the ERAD substrate, carboxypeptidase Y G255R (CPY*), and binds a model unfolded peptide ΔEspP and protein Δ131Δ in solution. Binding of Yos9 to these substrates results in their cooperative aggregation. Although the physiological consequences of this substrate-induced aggregation remain to be seen, it has the potential to play a role in the regulation of ERAD.

KEYWORDS:

Aggregation; CPY*; Carbohydrate-binding Protein; Endoplasmic Reticulum (ER); Endoplasmic Reticulum-associated Protein Degradation (ERAD); Substrate Specificity; Yos9

PMID:
25086047
PMCID:
PMC4162170
DOI:
10.1074/jbc.M114.583344
[Indexed for MEDLINE]
Free PMC Article

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