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PLoS One
2015 Nov 03;1011:e0140569. doi: 10.1371/journal.pone.0140569.
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Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs.
Zhu C
,
Nigam KB
,
Date RC
,
Bush KT
,
Springer SA
,
Saier MH
,
Wu W
,
Nigam SK
.
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The SLC22 family includes organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs). These are often referred to as drug transporters even though they interact with many endogenous metabolites and signaling molecules (Nigam, S.K., Nature Reviews Drug Discovery, 14:29-44, 2015). Phylogenetic analysis of SLC22 supports the view that these transporters may have evolved over 450 million years ago. Many OAT members were found to appear after a major expansion of the SLC22 family in mammals, suggesting a physiological and/or toxicological role during the mammalian radiation. Putative SLC22 orthologs exist in worms, sea urchins, flies, and ciona. At least six groups of SLC22 exist. OATs and OCTs form two Major clades of SLC22, within which (apart from Oat and Oct subclades), there are also clear Oat-like, Octn, and Oct-related subclades, as well as a distantly related group we term "Oat-related" (which may have different functions). Based on available data, it is arguable whether SLC22A18, which is related to bacterial drug-proton antiporters, should be assigned to SLC22. Disease-causing mutations, single nucleotide polymorphisms (SNPs) and other functionally analyzed mutations in OAT1, OAT3, URAT1, OCT1, OCT2, OCTN1, and OCTN2 map to the first extracellular domain, the large central intracellular domain, and transmembrane domains 9 and 10. These regions are highly conserved within subclades, but not between subclades, and may be necessary for SLC22 transporter function and functional diversification. Our results not only link function to evolutionarily conserved motifs but indicate the need for a revised sub-classification of SLC22.
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Fig 1. Unrooted Phylogeny of the SLC22 Transporter Family Using 163 Sequences of Various Organisms for Each of the 31 SLC22 Members.The sequences were aligned and the tree was generated using Clustal X 2.1 (using default parameters). The tree was viewed using Interactive Tree of Life (iTOL), an online tree viewing tool [55]. Accession numbers are listed in S1 Table. Bootstrap values are shown at each node of this phylogeny.
Fig 2. Shared Motifs of SLC22 Family Transporters by MEME Analysis on 16 of the Sequences Used in the Analysis.Abbreviations of the SLC22 member number is on the far left (e.g., A15 = SLC22A15) and known common names are on the far right. In green are the SLC22 family-conserved motifs which are lettered (A-P) in the order that they appear in the SLC22A6 amino acid sequence. The majority of the sequences follow this motif order. In red are the subclade-specific motifs overlaid on the same 1D representation of each SLC22 sequence. The first box labeled the Large Extracellular Loop represents the predicted Large Extracellular Loop [56] and the second box labeled the Large Intracellular Loop represents the predicted Large Intracellular Loop. Note that each 1D representation is proportionally scaled such that each sequence length can be estimated in the scale near the bottom of the figure.
Fig 3. Overlay of Common and Subclade-specific Motifs on Human SLC22A6 2D Topology.(A) SLC22 family-conserved motifs versus subclade-conserved motifs. Overlaid on the 2D topology are the 16 evolutionarily-conserved family motifs (green/dark green) and the 11 subclade-specific motifs (red/blue). Conserved family motifs are assigned letters A-P in the order of appearance in human OAT1 (human SLC22A6). Subclade-specific motifs are either whole or partial (red/blue) and are assigned the numbers 1–11. (B) This table describes the order, region, and percent present of the motifs which appear in the inputted set, MEME#, E-value, and amino acid sequence of each of the subclade-specific motifs identified for the hOAT1 sequence (red). (C) This table describes the SLC22 family-conserved motifs that have been overlaid onto the hOAT1 sequence (green). It lists the motif letter and percent present in all 111 sequences used in the MEME analysis, the MEME#, E-value, and the amino acid sequence of hOAT1 associated with the particular motif letter. Additional sequence information can be found in S3 and S4 Tables.
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