The ER protein folding sensor UDP-glucose glycoprotein–glucosyltransferase modifies substrates distant to local changes in glycoprotein conformation

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Abstract
We present in vitro data that explain the recognition mechanism of misfolded glycoproteins by UDP-glucose glycoprotein–glucosyltransferase (UGGT). The glycoprotein exo-(1,3)-β-glucanase (β-Glc) bearing two glycans unfolds in a pH-dependent manner to become a misfolded substrate for UGGT. In the crystal structure of this glycoprotein, the local hydrophobicity surrounding each glycosylation site coincides with the differential recognition of N-linked glycans by UGGT. We introduced a single F280S point mutation, producing a β-Glc protein with full enzymatic activity that was both recognized as misfolded and monoglucosylated by UGGT. Contrary to current views, these data show that UGGT can modify N-linked glycans positioned at least 40 Å from localized regions of disorder and sense subtle conformational changes within structurally compact, enzymatically active glycoprotein substrates.