Mechanistic insights into the acetyl-CoA recognition by SLC33A1
Apr. 11, 2025
Dr. Zhe Zhang published a review in Cell Discovery.
The structural biology analysis revealed that SLC33A1 exhibits characteristic MFS superfamily folding in its cytoplasm-facing conformation. The acetyl-CoA molecule is embedded in the central cavity of the transport channel in a bent conformation, with its 3′-phosphorylated ADP head stably bound through a hydrogen-bond network and π-π stacking interactions formed by key residues including Tyr225, Asn229, Tyr390, and Tyr418, while its pantetheine-thioethylamine tail displays dynamic flexibility. This "rigid anchoring-flexible adaptation" binding mode was validated through point mutation transport assays and molecular dynamics simulations. By integrating AlphaFold3-predicted lumen-facing conformation models with molecular dynamics simulations, the research team constructed a comprehensive transport cycle model, revealing the dynamic translocation process whereby SLC33A1 facilitates acetyl-CoA transport from cytoplasmic binding to luminal release through conformational changes.
This study has elucidated the substrate recognition mechanism of SLC33A1 at atomic resolution for the first time, not only providing crucial evidence for understanding the molecular basis of acetyl-CoA transmembrane transport, but also establishing a solid structural foundation for developing targeted therapeutic agents against related diseases.
Original link: https://www.nature.com/articles/s41421-025-00793-1