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bioRxiv · 10.1101/049825

Htm1p-Pdi1p is a folding sensitive mannosidase that marks N-glycoproteins for ER-associated protein degradation

Yi-Chang Liu·Danica Galonić Fujimori·Jonathan S. Weissman
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Abstract

Our understanding of how the endoplasmic reticulum-associated protein degradation (ERAD) machinery efficiently targets terminally misfolded proteins while avoiding the misidentification of nascent polypeptides and correctly folded proteins is limited. For luminal N-glycoproteins, demannosylation of their N-glycan to expose a terminal 1,6-linked mannose is necessary for their degradation via ERAD, but whether this modification is specific to misfolded proteins is unknown. Here we report that the Htm1p-Pdi1p complex acts as a folding-sensitive mannosidase for catalyzing this first committed step. We reconstitute this step in vitro with Htm1p-Pdi1p and model glycoprotein substrates whose structural states we can manipulate. We find that Htm1p-Pdi1p is a glycoprotein-specific mannosidase, which preferentially targets nonnative glycoproteins trapped in partially structured states. As such, Htm1p-Pdi1p is suited to act as a licensing factor that monitors folding in the ER lumen and preferentially commits glycoproteins trapped in partially structured states for degradation.

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Yi-Chang Liu, Danica Galonić Fujimori, Jonathan S. Weissman. 2016-04-22. Htm1p-Pdi1p is a folding sensitive mannosidase that marks N-glycoproteins for ER-associated protein degradation. https://doi.org/10.1101/049825

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