9N9J

Structure of a GRP94 folding intermediate engaged with a CCDC134- and FKBP11-bound secretory translocon

This is a non-PDB format compatible entry.

Summary for 9N9J

• Entry DOI: 10.2210/pdb9n9j/pdb
• EMDB information: 49171 72945
• Descriptor: Translocon-associated protein subunit alpha, Stress-associated endoplasmic reticulum protein 1, Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A, ... (78 entities in total)
• Functional Keywords: ribosome, membrane protein, translocon, transport, n-glycosylation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 70
• Total formula weight: 3334538.99

Authors

Yamsek, M.,Jha, R.,Keenan, R.J. (deposition date: 2025-02-10, release date: 2025-11-19, Last modification date: 2025-12-10)

Primary citation

Yamsek, M.,Ma, M.,Jha, R.,Wan, Y.,Li, Q.,Zhong, F.,DeLong, K.,Ji, Z.,Rohatgi, R.,Keenan, R.J.
Structural basis of regulated N-glycosylation at the secretory translocon.
Nature, 2025

PubMed Abstract: Most human secretory pathway proteins are N-glycosylated by oligosaccharyltransferase (OST) complexes as they enter the endoplasmic reticulum (ER). 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. 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.

PubMed: 41261126
DOI: 10.1038/s41586-025-09756-8

Experimental method

ELECTRON MICROSCOPY (3.2 Å)