TCB Publications - Abstract
David B Sauer, Noah Trebesch, Jennifer J Marden, Nicolette Cocco, Jinmei Song, Akiko Koide, Shohei Koide, Emad Tajkhorshid, and Da-Neng Wang. Structural basis for the reaction cycle of DASS dicarboxylate transporters. eLife, 9:e61350, 2020. (PMC: PMC7553777)
-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.
