Title: Structural basis for the DASS/SLC13 family’s carboxylate transport, chemical inhibition, and pathogenesis
Dr. David Sauer, P.I of Membrane Protein Structural and Chemical Biology, Centre for Medicines Discovery, University of Oxford.
Abstract: Citrate, α-ketoglutarate, and succinate are TCA cycle intermediates that also play essential roles in metabolic signalling and cellular regulation. These molecules are imported across the plasma membrane by the divalent anion sodium symporter (DASS) protein family, encoded by the SLC13 genes in humans. Underlining their biomedical importance, mutations in NaDC3 (SLC13A3) and NaCT (SLC13A5) result in neurological disorders. We determined several structures of two bacterial DASS proteins, including the previously unseen outward-facing state, to provide biophysical descriptions of the family’s elevator transport mechanism and strict substrate coupling. Building from this, we determined structures of the human citrate transporter NaCT in complexes with citrate or a small-molecule inhibitor. These revealed how the inhibitor arrests the transport cycle of NaCT, and explains compound selectivity. Together, the bacterial and NaCT structures provide a framework for understanding how various mutations abolish the transport activity and thereby cause SLC13A5-Epilepsy.
Monday, January 31, 2022 at 2:30 pm via Zoom
Hosted by: Dr. Seth Parker