Neurotransmitter Transporter homologue A.Yamashita(RIKEN)

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Neurotransmitter transporter homolog
–Structural basis for substrate recognition and transport inhibition–
YAMASHITA, ATSUKO1,2, Singh, Satinder, K.3, Kawate, Toshimitsu3, Jin, Yan2, and Gouaux, Eric3,4.
1RIKEN SPring-8 Center, Sayo, Hyogo 679-5148, Japan, 2Department of Biochemistry and Molecular Biophysics, Columbia
University, New York, New York 10032, USA, 3The Vollum Institute and 4HHMI, Oregon Health and Science University,
Portland, Oregon 97239, USA
In the central nervous system of vertebrates, synaptic transmission is terminated by uptake of
neurotransmitters from the synaptic cleft to the cytoplasm of neurons and glia catalyzed by specific
transporters. Na+/Cl--dependent neurotransmitter transporters (also referred to as neurotransmitter
sodium symporters; NSS) employ sodium and chloride electrochemical gradients to drive transport
of a wide array or substrates, including the biogenic amines (serotonin, dopamine, etc.) and amino
acids (GABA, glycine, etc.). Dysfunction of these transporters causes various psychiatric disorders,
including depression. NSS members are the targets of therapeutic agents for these diseases, such as
antidepressants. Although it has been highly required to understand the functional mechanisms of
NSS, structural analysis by X-ray crystallography has so far been hampered by the difficulties
generally encountered in membrane protein crystallization. To circumvent the problems, we
exploited the presence of bacterial homologs, because they were assumed to be more stable and
amenable to large-scale expression than the eukaryotic counterparts. The homologs have strict
conservation of residues essential to the function of NSS as well as clusters of highly conserved
sequences throughout the molecules, implying that they share similar architectures as well as
functional mechanisms with NSS. Among several bacterial homologs we cloned, we found a
highly-stable protein from Aquifex aeolicus, LeuT. LeuT is amenable to crystallographic structure
analysis and resulted atomic structural information of the state binding its substrates, L-leucine and
sodium ions, at 1.65 Å resolution [1]. Moreover, we also found that a tricyclic antidepressant
clomipramine inhibits substrate uptake by LeuT, and characterized its mechanism of action by flux,
binding, and crystallographic analyses [2]. In the symposium, we will discuss about mechanisms of
substrate recognition and transport inhibition of LeuT based on our recent structural and functional
studies.
[1] Yamashita, A., Singh, S. K., Kawate, T., Jin, Y., and Gouaux., E., Crystal structure of a bacterial homologue of
Na+/Cl--dependent neurotransmitter transporters. (2005) Nature 437, 215-223.
[2] Singh, S. K., Yamashita, A., and Gouaux, E., Antidepressant binding site in a bacterial homologue of neurotransmitter
transporters. (2007) Nature 448, 952-956.
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