Abstract
BackgroundABCB5 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 posses 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.Methodology/Principal FindingsWe 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.Conclusions/SignificanceFrom 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.
Highlights
ABCB5 is a member of the ATP-binding cassette (ABC) superfamily of transporters that function in the ATP-dependent transport of structurally diverse molecules
For ABCB5 beta we found that the transporter had 6 predicted TMs, one complete NBD and one incomplete NBD
The beta form was predicted to have 5 TM helices and the NBD was predicted to be on the extracellular surface, when we aligned the ABCB5 beta sequence to human Pgp we found that the topology predicted that the transporter would have 6TM helices instead of 5
Summary
ABCB5 is a member of the ATP-binding cassette (ABC) superfamily of transporters that function in the ATP-dependent transport of structurally diverse molecules. A number of transporters in this family are implicated in multidrug resistance and are recognized causes for the failure of cancer chemotherapy [1,2,3] These transporters represent the largest family of transmembrane proteins and are classified into seven families (A–G) in humans, based on the sequence and organization of the nucleotide-binding domain [4]. 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 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 posses 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
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