Testis-enhanced gene transfer family

The testis-enhanced gene transcript (TEGT) family includes the testis-enhanced gene transcript 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 Escherichia coli and the YetJ protein of Bacillus subtilis. These proteins are about 200-250 residues in length and exhibit 7 TMSs.[1]

Testis-enhanced gene transcript family
Identifiers
SymbolTEGT
PfamPF01027
TCDB1.A.14
OPM superfamily703
OPM protein4pgr

Homology

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) and the N-methyl-D-aspartate receptor glutamate binding chain, respectively. Two others are the rat neural membrane protein 35 and the Arabidopsis thaliana Bax inhibitor-1 (BI-1) protein capable of suppressing Bax-induced cell death in yeast.

BI-1

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.[2] 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. These proteins 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.[1]

Function

Based on experimental determination of the BI-1 topology, Bultynck et al. proposes that its C-terminal α-helical 20 amino acid peptide catalyzes Ca2+ flux both in vivo and in vitro.[2] The Ca2+-leak properties were conserved among animal, but not plant and yeast orthologs. By mutating one of the critical aspartate residues (D213) in the proposed Ca2+-channel pore in full-length BI-1, D213 proved to be essential for BI-1 dependent ER Ca2+-leak.

Structure

Chang et al. 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.[3] 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.[3]

Transport Reaction

The generalized reaction catalyzed by TEGT channels is:

cations (out) ⇌ cations (in)

References
  1. van Stelten J, Silva F, Belin D, Silhavy TJ (August 2009). "Effects of antibiotics and a proto-oncogene homolog on destruction of protein translocator SecY". Science. 325 (5941): 753–6. Bibcode:2009Sci...325..753V. doi:10.1126/science.1172221. PMC 2832214. PMID 19661432.
  2. 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, Methner A (January 2012). "The C terminus of Bax inhibitor-1 forms a Ca2+-permeable channel pore". The Journal of Biological Chemistry. 287 (4): 2544–57. doi:10.1074/jbc.M111.275354. PMC 3268414. PMID 22128171.
  3. Chang Y, Bruni R, Kloss B, Assur Z, Kloppmann E, Rost B, Hendrickson WA, Liu Q (June 2014). "Structural basis for a pH-sensitive calcium leak across membranes". Science. 344 (6188): 1131–5. Bibcode:2014Sci...344.1131C. doi:10.1126/science.1252043. PMC 4119810. PMID 24904158.

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