Glutamate transporters have a chloride channel with two hydrophobic gates
- 17 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 591 (7849), 327-331
- https://doi.org/10.1038/s41586-021-03240-9
Abstract
Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity1. The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism2,3,4,5. Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport6,7,8. However, the molecular mechanisms that enable these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is 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 information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family.Keywords
This publication has 85 references indexed in Scilit:
- Transient formation of water-conducting states in membrane transportersProceedings of the National Academy of Sciences of the United States of America, 2013
- Binding thermodynamics of a glutamate transporter homologNature Structural & Molecular Biology, 2013
- RELION: Implementation of a Bayesian approach to cryo-EM structure determinationJournal of Structural Biology, 2012
- Prevention of overfitting in cryo-EM structure determinationNature Methods, 2012
- Crystal structure of an asymmetric trimer of a bacterial glutamate transporter homologNature Structural & Molecular Biology, 2012
- Identification of the Third Na+ Site and the Sequence of Extracellular Binding Events in the Glutamate TransporterBiophysical Journal, 2010
- Transport mechanism of a bacterial homologue of glutamate transportersNature, 2009
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996