The cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold
Year: 2026
Type: article
Abstract: Proteins targeted at the secretory pathway are involved in a myriad of biological processes but can only do so when properly folded. Within the endoplasmic reticulum, glycoprotein folding is regulated by the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) and its oxidoreductase partner, the 15-kDa selenoprotein (SEP15, aka SELENOF). The interaction between these two chaperones is poorly understood, limiting understanding of their function. SEP15 is comprised of two domains, a C-terminal thioredoxin-like domain, the structure of which has been reported (PDB 2A4H), and an approximately 50-residue-long N-terminal Cys-rich domain (CRD), of unknown structure. Here, we report the NMR solution structure of the SEP15 CRD, which mediates the interaction with UGGT. These data reveal that this domain adopts a dimer in solution and forms a previously undescribed helical fold, stabilized by three disulfide bonds between residues C10-C42, C21-C43, and C24-C39. Furthermore, our results validate a model of the UGGT/SEP15 complex and lay the foundation for future studies of its interaction with glycoprotein substrates.
Source: Journal of Biological Chemistry
Institution: University of Massachusetts Amherst
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,430
Awards: Cellular protein maturation and degradation, G3120573784, Center for Biomolecular NMR Data Processing and Analysis, Chemistry Biology Interface Predoctoral Training Grant, Demystifying the interaction of UGGT, the ER folding gatekeeper, with its substrates and co-chaperone, Protein folding in the cell: Challenges and coping mechanisms
OpenAlex ID: W7221114875