The ups and downs of elevator-type di-/tricarboxylate membrane transporters

FEBS J. 2022 Mar;289(6):1515-1523. doi: 10.1111/febs.16158. Epub 2021 Aug 24.

Abstract

The divalent anion sodium symporter (DASS) family contains both sodium-driven anion cotransporters and anion/anion exchangers. The family belongs to a broader ion transporter superfamily (ITS), which comprises 24 families of transporters, including those of AbgT antibiotic efflux transporters. The human proteins in the DASS family play major physiological roles and are drug targets. We recently determined multiple structures of the human sodium-dependent citrate transporter (NaCT) and the succinate/dicarboxylate transporter from Lactobacillus acidophilus (LaINDY). Structures of both proteins show high degrees of structural similarity to the previously determined VcINDY fold. Conservation between these DASS protein structures and those from the AbgT family indicates that the VcINDY fold represents the overall protein structure for the entire ITS. The new structures of NaCT and LaINDY are captured in the inward- or outward-facing conformations, respectively. The domain arrangements in these structures agree with a rigid body elevator-type transport mechanism for substrate translocation across the membrane. Two separate NaCT structures in complex with a substrate or an inhibitor allowed us to explain the inhibition mechanism and propose a detailed classification scheme for grouping disease-causing mutations in the human protein. Structural understanding of multiple kinetic states of DASS proteins is a first step toward the detailed characterization of their entire transport cycle.

Keywords: DASS family; ITS; SLC13 family; citrate uptake; membrane transporter structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anions / metabolism
  • Dicarboxylic Acid Transporters / genetics
  • Dicarboxylic Acid Transporters / metabolism
  • Humans
  • Membrane Transport Proteins* / genetics
  • Sodium / metabolism
  • Symporters* / metabolism

Substances

  • Anions
  • Dicarboxylic Acid Transporters
  • Membrane Transport Proteins
  • Symporters
  • Sodium