Structural basis for the reaction cycle of DASS dicarboxylate transporters
David B Sauer, Noah Trebesch, Jennifer J Marden, Nicolette Cocco, Jinmei Song, Akiko Koide, Shohei Koide, Emad Tajkhorshid Is a corresponding author, Da-Neng Wang Is a corresponding author
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, United States; Department of Cell Biology, New York University School of Medicine, United States; NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, United States; Perlmutter Cancer Center, New York University School of Medicine, United States; Department of Medicine, New York University School of Medicine, United States; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, United States
Research Article Sep 1, 2020
Abstract
Citrate, α-ketoglutarate and succinate are TCA cycle intermediates that also play essential roles in metabolic signaling and cellular regulation. These di- and tricarboxylates are imported into the cell by the divalent anion sodium symporter (DASS) family of plasma membrane transporters, which contains both cotransporters and exchangers. While DASS proteins transport substrates via an elevator mechanism, to date structures are only available for a single DASS cotransporter protein in a substrate-bound, inward-facing state. We report multiple cryo-EM and X-ray structures in four different states, including three hitherto unseen states, along with molecular dynamics simulations, of both a cotransporter and an exchanger. Comparison of these outward- and inward-facing structures reveal how the transport domain translates and rotates within the framework of the scaffold domain through the transport cycle. Additionally, we propose that DASS transporters ensure substrate coupling by a charge-compensation mechanism, and by structural changes upon substrate release.
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