The Role of TM5 in Na2 Release and the Conformational Transition of Neurotransmitter:Sodium Symporters toward the Inward-Open State

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  • Sebastian Stolzenberg, Centre of Muscle & Bone Research, Charité-University Medicine Berlin, Campus Benjamin Franklin, Free University & Humboldt University Berlin, Berlin, Germany.
  • ,
  • Zheng Li, Weill Medical College of Cornell University, United States.
  • ,
  • Matthias Quick, Columbia University College of Physicians and Surgeons, United States.
  • ,
  • Lina Malinauskaite
  • ,
  • Poul Nissen
  • Harel Weinstein, Weill Medical College of Cornell University, United States.
  • ,
  • Jonathan A Javitch, Department of Epidemiology, Columbia University, New York, New York, United States of America.
  • ,
  • Lei Shi, NIH/NIDA-IRP, United States lei.shi2@nih.gov.

Neurotransmitter:sodium symporters (NSS) terminate neurotransmission by the reuptake of released neurotransmitters. This active accumulation of substrate against its concentration gradient is driven by the transmembrane Na+ gradient and requires that the transporter traverses several conformational states. LeuT, a prokaryotic NSS homolog, has been crystallized in outward-open, outward-occluded and inward-open states. Two crystal structures of another prokaryotic NSS homolog, the multi-hydrophobic amino acid transporter (MhsT) from Bacillus halodurans have been resolved in novel inward-occluded states, with the extracellular vestibule closed and the intracellular portion of TM5 (TM5i) in either an unwound or a helical conformation. We have investigated the potential involvement of TM5i in binding and unbinding of Na2, i.e. the Na(+) bound in the Na2 site, by carrying out comparative molecular dynamics simulations of the models derived from the two MhsT structures. We find that the helical TM5i conformation is associated with a higher propensity for Na2 release, which leads to the repositioning of the N terminus (NT) and transition to an inward-open state. By using comparative interaction network analysis, we also identify allosteric pathways connecting TM5i and the Na2 binding site to the extracellular and intracellular regions. Based on our combined computational and mutagenesis studies of MhsT and LeuT, we propose that TM5i plays a key role in Na2 binding and release associated with the conformational transition toward the inward-open state, a role that is likely to be shared across the NSS family.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind292
ISSN0021-9258
DOI
StatusUdgivet - 2017

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