Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 46, Pages 17214-17219Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602954103
Keywords
endoplasmic reticulum; winked glycoproteins; proteasome; protein degradation; deglycosylation
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Funding
- NIDDK NIH HHS [R01 DK054835, DK54835] Funding Source: Medline
- NIGMS NIH HHS [GM33814] Funding Source: Medline
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The inability of certain Winked glycoproteins to adopt their native conformation in the encloplasmic reticulum (ER) leads to their retrotranslocation into the cytosol and subsequent degradation by the proteasome. In this pathway the cytosolic peptide-N-glycanase (PNGase) cleaves the IN-linked glycan chains off denatured glycoproteins. PNGase is highly conserved in eukaryotes and plays an important role in ER-associated protein degradation. In higher eukaryotes, PNGase has an N-terminal and a C-terminal extension in addition to its central catalytic domain, which is structurally and functionally related to transglutaminases. Although the N-terminal domain of PNGase is involved in protein-protein interactions, the function of the C-terminal domain has not previously been characterized. Here, we describe biophysical, biochemical, and crystallographic studies of the mouse PNGase C-terminal domain, including visualization of a complex between this domain and mannopentaose. These studies demonstrate that the C-terminal domain binds to the mannose moieties of Winked oligosaccharicle chains, and we further show that it enhances the activity of the mouse PNGase core domain, presumably by increasing the affinity of mouse PNGase for the glycan chains of misfolded glycoproteins.
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