title: 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.
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.
authors.affiliation: Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems / Q000737:chemistry* / Q000378:metabolism*; D001419:Bacteria / Q000737:chemistry; D001665:Binding Sites; D017124:Conserved Sequence; D005057:Eukaryotic Cells / Q000737:chemistry*; D007930:Leucine / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000737:chemistry*; D011387:Prokaryotic Cells / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D026905:Amino Acid Transport Systems; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D007930:Leucine