9MUN

Structure of Human SLC33A1 in complex with oxidized glutathione

Summary for 9MUN

• Entry DOI: 10.2210/pdb9mun/pdb
• EMDB information: 48638
• Descriptor: Acetyl-coenzyme A transporter 1, OXIDIZED GLUTATHIONE DISULFIDE (2 entities in total)
• Functional Keywords: glutathione, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 62772.53

Authors

Gad, M.,Hite, R.K. (deposition date: 2025-01-14, release date: 2026-02-25, Last modification date: 2026-05-27)

Primary citation

Liu, S.,Gad, M.,Li, C.,Cho, K.,Liu, Y.,Wangdu, K.,Belay, V.,Millet, A.,Kojima, H.,Sanford, H.,Wolk, M.,Urnavicius, L.,Fedorova, M.,Patti, G.J.,Vinogradova, E.V.,Hite, R.K.,Birsoy, K.
SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
Nat.Cell Biol., 28:903-914, 2026

PubMed Abstract: The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

PubMed: 41998286
DOI: 10.1038/s41556-026-01922-y

Experimental method

ELECTRON MICROSCOPY (3.26 Å)