A conserved leucine occupies the empty substrate site of LeuT in the Na+-free return state

Lina Malinauskaite, Saida Said, Caglanur Sahin, Julie Grouleff, Azadeh Shahsavar, Henriette Bjerregaard, Pernille Noer, Kasper Severinsen, Thomas Boesen, Birgit Schiøtt, Steffen Sinning () and Poul Nissen ()
Additional contact information
Lina Malinauskaite: Danish Research Institute of Translational Neuroscience—DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University
Saida Said: Translational Neuropsychiatry Unit, Aarhus University
Caglanur Sahin: Danish Research Institute of Translational Neuroscience—DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University
Julie Grouleff: inSPIN and iNANO centers, Aarhus University
Azadeh Shahsavar: Danish Research Institute of Translational Neuroscience—DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University
Henriette Bjerregaard: Translational Neuropsychiatry Unit, Aarhus University
Pernille Noer: Translational Neuropsychiatry Unit, Aarhus University
Kasper Severinsen: Translational Neuropsychiatry Unit, Aarhus University
Thomas Boesen: Danish Research Institute of Translational Neuroscience—DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University
Birgit Schiøtt: inSPIN and iNANO centers, Aarhus University
Steffen Sinning: Translational Neuropsychiatry Unit, Aarhus University
Poul Nissen: Danish Research Institute of Translational Neuroscience—DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Bacterial members of the neurotransmitter:sodium symporter (NSS) family perform Na+-dependent amino-acid uptake and extrude H+ in return. Previous NSS structures represent intermediates of Na+/substrate binding or intracellular release, but not the inward-to-outward return transition. Here we report crystal structures of Aquifex aeolicus LeuT in an outward-oriented, Na+- and substrate-free state likely to be H+-occluded. We find a remarkable rotation of the conserved Leu25 into the empty substrate-binding pocket and rearrangements of the empty Na+ sites. Mutational studies of the equivalent Leu99 in the human serotonin transporter show a critical role of this residue on the transport rate. Molecular dynamics simulations show that extracellular Na+ is blocked unless Leu25 is rotated out of the substrate-binding pocket. We propose that Leu25 facilitates the inward-to-outward transition by compensating a Na+- and substrate-free state and acts as the gatekeeper for Na+ binding that prevents leak in inward-outward return transitions.

Date: 2016
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms11673 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11673

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms11673

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().