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Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms.

ABSTRACT: ABCB5 is a member of the ABC protein superfamily, which includes the transporters ABCB1, ABCC1 and ABCG2 responsible for causing drug resistance in cancer patients and also several other transporters that have been linked to human disease. The ABCB5 full transporter (ABCB5.ts) is expressed in human testis and its functional significance is presently unknown. Another variant of this transporter, ABCB5 beta possess a "half-transporter-like" structure and is expressed in melanoma stem cells, normal melanocytes, and other types of pigment cells. ABCB5 beta has important clinical implications, as it may be involved with multidrug resistance in melanoma stem cells, allowing these stem cells to survive chemotherapeutic regimes.We constructed and examined in detail topological structures of the human ABCB5 protein and determined in-silico the cSNPs (coding single nucleotide polymorphisms) that may affect its function. Evolutionary analysis of ABCB5 indicated that ABCB5, ABCB1, ABCB4, and ABCB11 share a common ancestor, which began duplicating early in the evolutionary history of chordates. This suggests that ABCB5 has evolved as a full transporter throughout its evolutionary history.From our in-silco analysis of cSNPs we found that a large number of non-synonymous cSNPs map to important functional regions of the protein suggesting that these SNPs if present in human populations may play a role in diseases associated with ABCB5. From phylogenetic analyses, we have shown that ABCB5 evolved as a full transporter throughout its evolutionary history with an absence of any major shifts in selection between the various lineages suggesting that the function of ABCB5 has been maintained during mammalian evolution. This finding would suggest that ABCB5 beta may have evolved to play a specific role in human pigment cells and/or melanoma cells where it is predominantly expressed.

SUBMITTER: Moitra K

PROVIDER: S-EPMC3029322 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms.

Moitra Karobi K Scally Mark M McGee Kate K Lancaster Germaine G Gold Bert B Dean Michael M

PloS one 20110127 1

<h4>Background</h4>ABCB5 is a member of the ABC protein superfamily, which includes the transporters ABCB1, ABCC1 and ABCG2 responsible for causing drug resistance in cancer patients and also several other transporters that have been linked to human disease. The ABCB5 full transporter (ABCB5.ts) is expressed in human testis and its functional significance is presently unknown. Another variant of this transporter, ABCB5 beta possess a "half-transporter-like" structure and is expressed in melanoma ...[more]

PMID: 21298007

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Project description:BackgroundSingle-nucleotide polymorphisms (SNPs) have a crucial function in affecting the susceptibility of individuals to diseases and also determine how an individual responds to different treatment options. The present study aimed to predict and characterize deleterious missense nonsynonymous SNPs (nsSNPs) of lysozyme C (LYZ C) gene using different computational methods. Lyz C is an important antimicrobial peptide capable of damaging the peptidoglycan layer of bacteria leading to osmotic shock and cell death. The nsSNPs were first analyzed by SIFT and PolyPhen v2 tools. The nsSNPs predicted as deleterious were then assessed by other in silico tools - SNAP, PROVEAN, PhD-SNP, and SNPs & GO. These SNPs were further examined by I-Mutant 3.0 and ConSurf. GeneMANIA and STRING tools were used to study the interaction network of the LYZ C gene. NetSurfP 2.0 was used to predict the secondary structure of Lyz C protein. The impact of variations on the structural characteristics of the protein was studied by HOPE analysis. The structures of wild type and variants were predicted by SWISS-MODEL web server, and energy minimization was carried out using XenoPlot software. TM-align tool was used to predict root-mean-square deviation (RMSD) and template modeling (TM) scores.ResultsEight missense nsSNPs (T88N, I74T, F75I, D67H, W82R, D85H, R80C, and R116S) were found to be potentially deleterious. I-Mutant 3.0 determined that the variants decreased the stability of the protein. ConSurf predicted rs121913547, rs121913549, and rs387906536 nsSNPs to be conserved. Interaction network tools showed that LYZ C protein interacted with lactoferrin (LTF). HOPE tool analyzed differences in physicochemical properties between wild type and variants. TM-align tool predicted the alignment score, and the protein folding was found to be identical. PyMOL was used to visualize the superimposition of variants over wild type.ConclusionThis study ascertained the deleterious missense nsSNPs of the LYZ C gene and could be used in further experimental analysis. These high-risk nsSNPs could be used as molecular targets for diagnostic and therapeutic interventions.

Dataset Information

Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms.

Publications

Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms.

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