The cation/Ca$^2+$ exchanger superfamily: phylogenetic analysis
and structural implications.
Mol. Biol. Evol., 21 (9):
1692--1703 (September 2004)DOI: 10.1093/molbev/msh177
Abstract
Cation/Ca$^2+$ exchangers are an essential component of Ca$^2+$
signaling pathways and function to transport cytosolic Ca$^2+$
across membranes against its electrochemical gradient by utilizing
the downhill gradients of other cation species such as H$^+$, Na$^+$,
or K$^+$. The cation/Ca$^2+$ exchanger superfamily is composed
of H$^+$/Ca$^2+$ exchangers and Na$^+$/Ca$^2+$ 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/Ca$^2+$ 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/Ca$^2+$
exchanger superfamily of 147 sequences. The results present a framework
for structure-function relationships of cation/Ca$^2+$ exchangers,
suggesting unique signature motifs of conserved residues that may
underlie divergent functional properties. Construction of a phylogenetic
tree with inclusion of cation/Ca$^2+$ exchangers with known functional
properties defines five protein families and the evolutionary relationships
between the members. Based on this analysis, the cation/Ca$^2+$
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/Ca$^2+$
exchangers.
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