1.A.14 The Calcium Transporter A (CaTA) (formerly the Testis-Enhanced Gene Transfer (TEGT)) Family
The CaTA family (also called the BI-1/YccA family; formerly the TEGT family (SwissProt family UPF0005; Prosite entry PDOC00957)) includes members represented in all three domains of life. One of these proteins, TEGT or the Bax Inhibitor-1 (TC# 1.A.14.1.1), has a C-terminal domain that forms a Ca2+-permeable channel (Bultynck et al., 2011). These proteins are about 200-250 residues in length and exhibit 7 TMSs. They include the testis-enhanced gene transfer proteins of mammals which are expressed at high levels in the testis, the putative glutamate/aspartate binding proteins of plants and animals, the YccA protein of E. coli and the YetJ protein of Bacillus subtilis. They are distantly related to the ionotropic glutamate-binding protein of the N-methyl D-aspartate (NMDA) receptor of man. Homologues include a putative cold shock inducible protein and a SecY stabilizing protein (van Stelten et al., 2009). Bacterial CaTA (BI-1) domains are found in 'fusion' proteins of histidine sensor kinases, diguanylate cyclases and proteins with ABC2-like P-loop ATPase domains. Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) proteins that mediate Ca2+ homeostasis and cell death have been reviewed (Liu 2017).
A bacterial member of the CaTA family has been partially characterized. This is the YbhL protein of E coli. It is 234 aas long, exhibits 7 putative TMSs and may stimulate glucose (and fructose?) uptake or metabolism in E. coli. It plays a role in preventing E. coli cell death in the stationary phase of growth (M. Inouye, personal communication).
Homologues are found in a variety of Gram-negative and Gram-positive bacteria, yeast, fungi, plants, animals and viruses. The E. coli genome encodes three paralogues, YbhL, YbhM and YccA. Distant homologues found in Drosophilia melanogaster and the rat are the N-methyl-D-aspartate receptor-associated protein (NMDARAI) (203 aas; pirS53708) and the N-methyl-D-aspartate receptor glutamate binding chain (516 aas; pirS19586), respectively. Two others are the rat neural membrane protein 35 (NMP35) (gbAF044201) and the Arabidopsis thaliana Bax inhibitor-1 (BI-1) protein capable of suppressing Bax-induced cell death in yeast (S. cerevisiae) (247 aas; gbAB025927). Most of the more closely related homologues of the E. coli SAD protein are of 200-250 aas.
Bax Inhibitor-1 (BI-1) is an ER-localized protein that protects against apoptosis and ER stress. BI-1 has been proposed to modulate ER Ca2+ homeostasis by acting as a Ca2+-leak channel. Based on experimental determination of the BI-1 topology, Bultynck et al. (2011) proposed that its C-terminal α-helical 20 aa peptide catalyzes Ca2+ flux both in vivo and in vitro. The Ca2+-leak properties were conserved among animal, but not plant and yeast orthologs. By mutating one of the critical aspartate residues in the proposed Ca2+-channel pore in full-length BI-1, D213 proved to be essential for BI-1 dependent ER Ca2+-leak.
Calcium homeostasis balances passive calcium leak and active calcium uptake. Human Bax inhibitor-1, BI-1, an antiapoptotic protein, is representative of a highly conserved and widely distributed family, the transmembrane Bax inhibitor motif (TMBIM) proteins. Chang et al. 2014 published crystal structures of a bacterial homolog, YetJ (TC# 1.A.14.2.3) at 1.9 Å resolution and characterized its calcium leak activity. Its seven-transmembrane-helix fold features two triple-helix sandwiches wrapped around a central C-terminal helix. Structures obtained in closed and open conformations are reversibly interconvertible by changes in the pH. A hydrogen-bonded perturbed pair of conserved aspartyl residues explains the pH dependence of this transition, and the pH regulates calcium influx in proteoliposomes. Homology models for human BI-1 provided insight into its cytoprotective activity (Chang et al. 2014).
The generalized reaction catalyzed by TEGT channels is:
cations (out) ⇌ cations (in)