Structural basis of regulated N-glycosylation at the secretory translocon.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41261126.
- Also identified by DOI 10.1038/s41586-025-09756-8 and PMC identifier 12804085.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Most human secretory pathway proteins are N-glycosylated by oligosaccharyltransferase (OST) complexes as they enter the endoplasmic reticulum (ER)<sup>1-3</sup>. Recent work revealed a substrate-assisted mechanism by which N-glycosylation of the chaperone glucose-regulated protein 94 (GRP94) is regulated to control cell surface receptor signalling<sup>4</sup>. Here we report the structure of a natively isolated GRP94 folding intermediate tethered to a specialized CCDC134-bound translocon. Together with functional analysis, the data reveal how a conserved N-terminal extension in GRP94 inhibits OST-A and how structural rearrangements within the translocon shield the tethered nascent chain from inappropriate OST-B glycosylation. These interactions depend on a hydrophobic CCDC134 groove, which recognizes a non-native conformation of nascent GRP94. Our results define a mechanism of regulated N-glycosylation and illustrate how the nascent chain remodels the translocon to facilitate its own biogenesis.
Medical subject headings
- Membrane Proteins
- HSP70 Heat-Shock Proteins
- Secretory Pathway
- Membrane Glycoproteins