Format

Send to

Choose Destination
Nat Struct Mol Biol. 2014 Nov;21(11):1006-12. doi: 10.1038/nsmb.2894. Epub 2014 Oct 5.

A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters.

Author information

1
1] Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark. [2] Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
2
1] Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
3
Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA.
4
1] Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA. [4] Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Abstract

Neurotransmitter/sodium symporters (NSSs) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters. Key conformational states have been reported for the bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, an NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-tryptophan, providing insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. We propose a mechanism, based on our structural and functional findings, in which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state.

PMID:
25282149
PMCID:
PMC4346222
DOI:
10.1038/nsmb.2894
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center