Oral Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Glutamate transporters contain a conserved chloride channel with two hydrophobic gates (#15)

Ichia Chen 1 , Shashank Pant 2 , Qianyi Wu 1 , Rosemary Cater 3 , Meghna Sobti 4 , Robert Vandenberg 1 , Alastair Stewart 4 , Emad Tajkhorshid 2 , Josep Font Sadurni 1 , Renae Ryan 1
  1. Discipline of Pharmacology, School of Medical Science, University of Sydney, NSW, Australia
  2. NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
  3. Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA
  4. Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Insitute, Darlinghurst, NSW, Australia

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, therefore its precise control is vital for maintaining normal brain function and preventing excitotoxicity. Removal of extracellular glutamate is achieved by plasma membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism. Glutamate transporters also conduct chloride ions via a channel-like process that is thermodynamically uncoupled from transport. However, the molecular mechanisms that allow these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here, for the first time, we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, revealing an aqueous cavity that is formed during the transport cycle. Using functional studies and molecular dynamics simulations, we show that this cavity is an aqueous-accessible chloride permeation pathway gated by two hydrophobic regions, and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function and add a crucial piece of information to aid mapping of the complete transport cycle shared by the SLC1A transporter family.1, 2

 

 

 

  1. Glutamate transporters contain a conserved chloride channel with two hydrophobic gates. Chen.i, et al. BioRxiv. doi: 10.1101/2020.05.25.115360
  2. This paper is under review in Nature. (Nature 2020-05-09637A)