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Research ArticleArticle

A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function

Thijs Beuming, Lei Shi, Jonathan A. Javitch and Harel Weinstein
Molecular Pharmacology November 2006, 70 (5) 1630-1642; DOI: https://doi.org/10.1124/mol.106.026120
Thijs Beuming
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Lei Shi
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Jonathan A. Javitch
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Harel Weinstein
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Abstract

The recently elucidated crystal structure of a prokaryotic member of the neurotransmitter/sodium symporter (NSS) family (Yamashita et al., 2005) is a major advance toward understanding structure-function relationships in this important class of transporters. To aid in the generalization of these results, we present here a comprehensive sequence alignment of all known prokaryotic and eukaryotic NSS proteins, based on the crystal structure of the leucine transporter from Aquifex aeolicus (LeuT). Regions of low sequence identity between prokaryotic and eukaryotic transporters were aligned with the aid of a number of bioinformatics tools, and the resulting alignments were validated by comparison with experimental data. In a number of regions, including the transmembrane segments 4, 5, and 9 as well as extracellular loops 2, 3, and 4, our alignment differs from the one proposed previously [Nature (Lond)437: 215-223, 2005]. Important similarities and differences among the sequences of NSS proteins in regions likely to determine selectivity in substrate binding and mechanisms of transport regulation are discussed in the context of the LeuT structure and the alignment.

Footnotes

  • This work was supported by National Institutes of Health grants P01-DA12408, R01-DA11495 and R01-DA17293, K02-MH57324, and K05-DA00060.

  • T.B. and L.S. contributed equally, and J.A.J. and H.W. contributed equally.

  • ABBREVIATIONS: NSS, neurotransmitter/sodium symporter; DAT, dopamine transporter; NET, norepinephrine transporter; SERT, serotonin transporter; TM, transmembrane segment; MTSEA, methanethiosulfonate ethylammonium; MTS, methanethiosulfonate; GAT, GABA transporter.

    • Received May 4, 2006.
    • Accepted July 31, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function

Thijs Beuming, Lei Shi, Jonathan A. Javitch and Harel Weinstein
Molecular Pharmacology November 1, 2006, 70 (5) 1630-1642; DOI: https://doi.org/10.1124/mol.106.026120

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Research ArticleArticle

A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function

Thijs Beuming, Lei Shi, Jonathan A. Javitch and Harel Weinstein
Molecular Pharmacology November 1, 2006, 70 (5) 1630-1642; DOI: https://doi.org/10.1124/mol.106.026120
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