4.8 Article

Structural basis for the reaction cycle of DASS dicarboxylate transporters

Journal

ELIFE
Volume 9, Issue -, Pages -

Publisher

ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.61350

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Funding

  1. National Institutes of Health [R01NS108151, R01GM121994, R01DK099023, U54GM095315, P41GM104601, R01GM067887, T32GM088118, R01GM123455]
  2. TESS Research Foundation
  3. American Epilepsy Society [AES2017SD3]
  4. American Cancer Society [129844-PF-17-135-01-TBE]
  5. Department of Defense [W81XWH-16-1-0153]
  6. National Science Foundation [1746047]
  7. XSEDE [TG-MCA06N060]
  8. Blue Waters
  9. Direct For Education and Human Resources
  10. Division Of Graduate Education [1746047] Funding Source: National Science Foundation

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Citrate, a-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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