Evolution of the ATP-binding-cassette transmembrane transporters of vertebrates

The ATP-binding-cassette transmembrane transporters (ABC transporters)known from vertebrates belong to four major subfamilies: (1) the P-glycoproteins (Pgp); (2) the cystic fibrosis transmembrane conductanceregulators (CFTR); (3) the Tap proteins encoded with the majorhistocompatibility complex of mammals; and (4) the peroxisomal membraneproteins. Both Pgp and CFTR have a structure suggesting a past internalgene duplication; a phylogenetic analysis indicated that these duplicationsoccurred independently, while an independent tandem gene duplicationoccurred in the case of the Tap family. Both the Pgp and Tap proteins showevidence of relationship to bacterial ABC transporters lacking internalduplication, and both are significantly more closely related to the HlyBand MsbA families of transporters from purple bacteria than they are to ABCtransporters from nonpurple bacteria. The simplest hypothesis to explainthis observation is that eukaryotic Pgp and Tap genes are descended from amitochondrial gene or genes that were subsequently translocated to thenuclear genome. The Pgp genes of eukaryotes are characterized by aremarkable degree of convergent evolution between the ATP-binding cassettesof their N- terminal and C-terminal halves, whereas no such convergence isseen between the two halves of CFTR genes or between the duplicated Tapgenes. Exon 13 of the CFTR gene, which encodes a putative regulatory domainnot found in other ABC transporters apart from CFTR, showed high levels ofboth synonymous and nonsynonymous difference in comparisons among differentmammalian species, suggesting that this region is a mutational hot spot.