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From Proteopedia
Crystal structure of the GltPh V216C-G388C mutant cross-linked with divalent mercury
Structural highlights
FunctionGLT_PYRHO Sodium-dependent, high-affinity amino acid transporter that mediates aspartate uptake (PubMed:17435767, PubMed:19380583, PubMed:17230192, Ref.11). Has only very low glutamate transport activity (PubMed:19380583, PubMed:17230192). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions, resulting in electrogenic transport (PubMed:17435767, PubMed:19380583, Ref.11). Na(+) binding enhances the affinity for aspartate (PubMed:19380583, Ref.11). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:17435767). In contrast to mammalian homologs, transport does not depend on pH or K(+) ions (PubMed:19380583).[1] [2] [3] [PDB:4P19] Publication Abstract from PubMedGlutamate 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 excitotoxicity(1). 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 mechanism(2-5). Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport(6-8). 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. Glutamate transporters have a chloride channel with two hydrophobic gates.,Chen I, Pant S, Wu Q, Cater RJ, Sobti M, Vandenberg RJ, Stewart AG, Tajkhorshid E, Font J, Ryan RM Nature. 2021 Feb 17. pii: 10.1038/s41586-021-03240-9. doi:, 10.1038/s41586-021-03240-9. PMID:33597752[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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