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

Autor: Sauer DB; Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY, USA.; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, UK., Wang B; Cryo-Electron Microscopy Core, New York University School of Medicine, NY, USA., Sudar JC; Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY, USA., Song J; Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY, USA., Marden J; Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY, USA., Rice WJ; Cryo-Electron Microscopy Core, New York University School of Medicine, NY, USA., Wang DN; Skirball Institute of Biomolecular Medicine, New York University School of Medicine, NY, USA.; Department of Cell Biology, New York University School of Medicine, NY, USA.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2022 Mar; Vol. 289 (6), pp. 1515-1523. Date of Electronic Publication: 2021 Aug 24.
DOI: 10.1111/febs.16158
Abstrakt: 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.
(© 2021 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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