The Cation/Ca2+ Exchanger Superfamily: Phylogenetic Analysis and Structural Implications

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Abstract
Cation/Ca2+ exchangers are an essential component of Ca2+ signaling pathways and function to transport cytosolic Ca2+ across membranes against its electrochemical gradient by utilizing the downhill gradients of other cation species such as H+, Na+, or K+. The cation/Ca2+ exchanger superfamily is composed of H+/Ca2+ exchangers and Na+/Ca2+ exchangers, which have been investigated extensively in both plant cells and animal cells. Recently, information from completely sequenced genomes of bacteria, archaea, and eukaryotes has revealed the presence of genes that encode homologues of cation/Ca2+ exchangers in many organisms in which the role of these exchangers has not been clearly demonstrated. In this study, we report a comprehensive sequence alignment and the first phylogenetic analysis of the cation/Ca2+ exchanger superfamily of 147 sequences. The results present a framework for structure-function relationships of cation/Ca2+ exchangers, suggesting unique signature motifs of conserved residues that may underlie divergent functional properties. Construction of a phylogenetic tree with inclusion of cation/Ca2+ exchangers with known functional properties defines five protein families and the evolutionary relationships between the members. Based on this analysis, the cation/Ca2+ exchanger superfamily is classified into the YRBG, CAX, NCX, and NCKX families and a newly recognized family, designated CCX. These findings will provide guides for future studies concerning structures, functions, and evolutionary origins of the cation/Ca2+ exchangers.