%0 Journal Article
%T Animal Ca2+ release-activated Ca2+ (CRAC) channels appear to be homologous to and derived from the ubiquitous cation diffusion facilitators
%A Madeleine G Matias
%A Kenny M Gomolplitinant
%A Dorjee G Tamang
%A Milton H Saier
%J BMC Research Notes
%D 2010
%I BioMed Central
%R 10.1186/1756-0500-3-158
%X CDF antiporters derived from a primordial 2 transmembrane spanner (TMS) hairpin structure by intragenic triplication to yield 6 TMS proteins. Four programs (IC/GAP, GGSEARCH, HMMER and SAM) were evaluated for identifying sequence similarity and establishing homology using statistical means. Overall, the order of sensitivity (similarity detection) was IC/GAP = GGSEARCH > HMMER > SAM, but the use of all four programs was superior to the use of any two or three of them. Members of the CDF family appeared to be homologous to members of the 4 TMS Orai channel proteins.CRAC channels derived from CDF carriers by loss of the first two TMSs of the latter. Based on statistical analyses with multiple programs, TMSs 3-6 in CDF carriers are homologous to TMSs 1-4 in CRAC channels, and the former was the precursor of the latter. This is an unusual example of how a functionally and structurally more complex protein may have predated a simpler one.Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting an immune response to pathogens [1]. Cells from patients with one form of the hereditary Severe Combined Immune Deficiency (SCID) syndrome are defective in Store-Operated Ca2+ (SOC) entry and CRAC channel function [2]. The genetic defect in these patients appears to be in a protein called Orai1, which contains four putative transmembrane segments (TMSs) [3]. SCID patients are homozygous for a single missense mutation in Orai1 (TC# 1.A.52.1.1), and expression of wild-type Orai1 in SCID T cells restores SOC influx and the CRAC current. Orai1 is an essential component of the CRAC channel complex [4,5].Human Orai1 has homologues in all animals with sequenced genomes, and these channel proteins have been identified largely in animals. They interact with Stromal Interaction Molecule 1 (STIM1) to form the functional channel complex [5-8]. One study concluded that Orai1 forms a homotetramer [9]. Coupling of STIM1 to SOC entry dep
%U http://www.biomedcentral.com/1756-0500/3/158