Abstract
The endoplasmic reticulum (ER) possesses a protein quality control system that supports the efficient folding of newly synthesized glycoproteins. In this system, a series of N-linked glycan intermediates displayed on proteins serve as quality tags. The ER folding-sensor enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) operates as the gatekeeper for ER quality control by specifically transferring monoglucose residues to incompletely folded glycoproteins, thereby allowing them to interact with lectin chaperone complexes to facilitate their folding. Despite its functional importance, no structural information is available for this key enzyme to date. To elucidate the folding-sensor mechanism in the ER, we performed a structural study of UGGT. Based on bioinformatics analyses, the folding-sensor region of UGGT was predicted to harbour three tandem thioredoxin (Trx)-like domains, which are often found in proteins involved in ER quality control. Furthermore, we determined the three-dimensional structure of the third Trx-like domain, which exhibits an extensive hydrophobic patch concealed by its flexible C-terminal helix. Our structural data suggest that this hydrophobic patch is involved in intermolecular interactions, thereby contributing to the folding-sensor mechanism of UGGT.
Highlights
Structural insight into substrate recognition by the endoplasmic reticulum folding-sensor enzyme: crystal structure of third thioredoxin-like domain of UDP-glucose:glycoprotein glucosyltransferase
The monoglucosylated D1 branch, an intermediate generated during this process, exhibits a critical determinant recognized by oxidoreductase (ERp57)-associated lectins, i.e. calnexin (CNX) and/or calreticulin (CRT)
UDP-glucose:glycoprotein glucosyltransferase (UGGT) is a large enzyme, comprising approximately 1500 amino acid residues, which has been putatively divided into two regions: an N-terminal folding-sensor region, which accounts for approximately 80% of the enzyme and is not homologous with any known structures, and a C-terminal catalytic domain, which accounts for the remaining 20% of the enzyme and belongs to the glycosyltransferase 8 family[19,20]
Summary
Structural insight into substrate recognition by the endoplasmic reticulum folding-sensor enzyme: crystal structure of third thioredoxin-like domain of UDP-glucose:glycoprotein glucosyltransferase. The endoplasmic reticulum (ER) possesses a protein quality control system that supports the efficient folding of newly synthesized glycoproteins In this system, a series of N-linked glycan intermediates displayed on proteins serve as quality tags. The ER folding-sensor enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) operates as the gatekeeper for ER quality control by transferring monoglucose residues to incompletely folded glycoproteins, thereby allowing them to interact with lectin chaperone complexes to facilitate their folding. UDP-glucose:glycoprotein glucosyltransferase (UGGT) catalyzes reglucosylation, thereby regenerating monoglucosylated glycoforms, which are able to revisit the chaperone complex[7,12,13,14,15,16,17,18] This glucose-trimming and -tagging process is called the ‘CNX/CRT cycle’. The structural basis of the working mechanism of the CNX/CRT cycle remains unclear
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