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

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  • Lina Malinauskaite, 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., Denmark
  • Matthias Quick, 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.
  • ,
  • Linda Reinhard, 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., Unknown
  • Joseph A Lyons
  • Hideaki Yano, Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA., Unknown
  • Jonathan A Javitch, 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.
  • ,
  • Poul Nissen

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.

Original languageEnglish
JournalNature Structural and Molecular Biology
Volume21
Issue11
Pages (from-to)1006-1012
Number of pages7
ISSN1545-9993
DOIs
Publication statusPublished - Nov 2014

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