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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)

 

 

References associated with 1.A.14 family:

Bultynck G., Kiviluoto S., Henke N., Ivanova H., Schneider L., Rybalchenko V., Luyten T., Nuyts K., De Borggraeve W., Bezprozvanny I., Parys JB., De Smedt H., Missiaen L. and Methner A. (2012). The C terminus of Bax inhibitor-1 forms a Ca2+-permeable channel pore. J Biol Chem. 287(4):2544-57. 22128171
Büttner, S., D. Ruli, F.N. Vögtle, L. Galluzzi, B. Moitzi, T. Eisenberg, O. Kepp, L. Habernig, D. Carmona-Gutierrez, P. Rockenfeller, P. Laun, M. Breitenbach, C. Khoury, K.U. Fröhlich, G. Rechberger, C. Meisinger, G. Kroemer, and F. Madeo. (2011). A yeast BH3-only protein mediates the mitochondrial pathway of apoptosis. EMBO. J. 30: 2779-2792. 21673659
Carrara G., Saraiva N., Parsons M., Byrne B., Prole DL., Taylor CW. and Smith GL. (2015). Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration. J Biol Chem. 290(18):11785-801. 25713081
Chang, Y., R. Bruni, B. Kloss, Z. Assur, E. Kloppmann, B. Rost, W.A. Hendrickson, and Q. Liu. (2014). Structural basis for a pH-sensitive calcium leak across membranes. Science 344: 1131-1135. 24904158
Jin, L., M. Miyazaki, S. Mizuno, M. Takigawa, T. Hirose, K. Nishimura, T. Toida, K. Williams, K. Kashiwagi, and K. Igarashi. (2008). The pore region of N-methyl-D-aspartate receptors differentially influences stimulation and block by spermine. J Pharmacol Exp Ther 327: 68-77. 18632991
Kota K., Kuzhikandathil EV., Afrasiabi M., Lacy B., Kontoyianni M., Crider AM. and Song D. (2015). Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor. Pharmacol Res. 99:174-184. 26116441
Liu, Q. (2017). TMBIM-mediated Ca2+ homeostasis and cell death. Biochim. Biophys. Acta. [Epub: Ahead of Print] 28064000
M''Angale, P.G. and B.E. Staveley. (2016). Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster. Genet Mol Res 15:. 28002605
van Stelten, J., F. Silva, D. Belin, and T.J. Silhavy. (2009). Effects of antibiotics and a proto-oncogene homolog on destruction of protein translocator SecY. Science 325: 753-756. 19661432