TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.A.14.1.1









The Bax Inhibitor-1, BI-1 of 311 aas (or 237 aas; P55061) and 6 TMSs; it is also called the testis-enhanced gene transcript (TEGT) protein or the transmembrane BAX inhibitor motif-containing protein 6 (TMBIM6).  It forms an ER, pH-sensitive, cation-selective, Ca2+-permeable leak channel (Bultynck et al., 2011; Chang et al. 2014).  Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015). The TMBIM6 calcium leak channel activity negatively regulates autophagy and autophagosome formation, influencing cardovascular traits (Swain et al. 2020). It enhances autophagy through regulation of lysosomal calcium (Kim et al. 2020). A TMBIM6 deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1alpha. Its overexpression improves glucose metabolism, and knockout mice develop obesity (Philippaert et al. 2020). TMBIM6 knockout mice feature high glucose-stimulated insulin secretion in vivo. This coincides with profound changes in glucose-mediated Ca2+ regulation in isolated pancreatic beta cells and increases levels of IRE1alpha levels. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca2+ release channel in the ER. Thus, TMBIM6(-/-) leads to obesity and hepatic steatosis by blocking Ca2+ transport (Philippaert et al. 2020). The mammalian Transmembrane BAX Inhibitor Motif (TMBIM) protein family in humans consists of six evolutionarily conserved hydrophobic proteins that affect programmed cell death and the regulation of intracellular calcium levels (Zhang et al. 2021). There are seven TMBIM family members in Drosophila melanogaster. Tmbim5 and 6 are essential for fly development and survival but affect cell survival through different mechanisms (Zhang et al. 2021). It prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury (Zhou et al. 2023).

Eukaryota
Metazoa, Chordata
BI-1 or TEGT of Homo sapiens (P55061)
1.A.14.1.2









Uncharacterized protein of 304 aas and 7 TMSs.

Eukaryota
Euglenozoa
UP of Trypanosoma cruzi marinkellei
1.A.14.1.3









Uncharacterized protein of 238 aas and 7 TMSs

Eukaryota
Apicomplexa
UP of Babesia microti
1.A.14.1.4









Uncharacterized protein of 317 aas and 7 TMSs

Eukaryota
Haptophyta
UP of Emiliania huxleyi
1.A.14.1.5









Growth hormone-inducible membrane protein of 345 aas and 8 putative TMSs

Eukaryota
Metazoa, Chordata
GH-inducible membrahe protein of Anas platyrhynchos (Mallard) (Anas boschas)
1.A.14.1.6









Putative Bax inhibitor of 213 aas and 7 TMSs

Eukaryota
Evosea
Putative Bax inhibitor of Entamoeba histolytica
1.A.14.2.1









The YccA protein, an inhibitor of FtsH. May share a similar mechanism of action as BI-1 in regulation apoptsis upon prolonged secretion stress (van Stelten et al., 2009).

Bacteria
Pseudomonadota
YccA of E. coli (P0AAC6)
1.A.14.2.2









The YbhL (AceP) protein. Possibly a pmf-dependent acetate uptake transporter. [14C]Acetate uptake was inhibited by CCCP as well as cold acetate, serine, α-ketoglutarate, lactate, and succinate (M. Inouye, personal communication).

Bacteria
Pseudomonadota
YbhL of E. coli (P0AAC4)
1.A.14.2.3









The 7 TMS proton-sensitive Ca2+ leak channel, YetJ.  The activity and high resolution 3-d structure have been determined (Chang et al. 2014). BsYetJ in lipid nanodiscs is structurally different from those crystallized in detergents. Li et al. 2020 showed that the BsYetJ conformation is pH-sensitive in the apo state (lacking calcium), whereas in a calcium-containing solution, it is stuck in an intermediate state, inert to pH changes. Only when the transmembrane calcium gradient is established can the calcium-release activity of holo-BsYetJ occur and be mediated by pH-dependent conformational changes, suggesting a dual gating mechanism. Conformational substates involved in the process and a key residue, D171, relevant to the gating of calcium were identified. Thus, BsYetJ/TMBIM6 is a pH-dependent, voltage-gated calcium channel (Li et al. 2020). The transmembrane BAX inhibitor-1-containing motif 6 (TMBIM6) protein may modulate apoptosis by regulating calcium homeostasis in the endoplasmic reticulum (ER). Lan et al. 2023 investigated all negatively charged residues in BsYetJ, a bacterial homolog of TMBIM6. They reconstituted BsYetJ in membrane vesicles with a lipid composition similar to that of the ER. The charged residues E49 and R205 work together as a major gate, regulating calcium conductance in these ER-like lipid vesicles. However, these residues become largely inactive when reconstituted in other lipid environments. D195 acts as a minor filter compared to the E49-R205 dyad (Lan et al. 2023).

Bacteria
Bacillota
YetJ of Bacillus subtilis (O31539)
1.A.14.2.4









Uncharacterized protein, YbhM, of 237 aas and 7 TMSs.  The ybhM gene is adjacent to the homologous ybhL gene (TC# 1.A.14.2.2), and another  homologous gene is inbetween these two; these two or three genes could function together as a single transporter. 

Bacteria
Pseudomonadota
YbhM of E. coli
1.A.14.2.5









Protein of 234 aas and 7 TMSs encoded by a gene between and homologous to YbhL and YbhM. In the Pfam family Bax1-I.

Bacteria
Pseudomonadota
Bax1-I protein of E. coli
1.A.14.2.6









Uncharacterized protein of 227 aas and 7 TMSs

Bacteria
Bacillota
UP of Streptococcus sanguinis
1.A.14.2.7









Bax inhibitor-1, BI1/YccA homologue of 245 aas and 7 TMSs in a 1 + 1 + 2 + 2 + 1 TMS arrangement. BrBI is a bacterial cytoprotective protein involved in membrane homeostasis, cell division, and stress resistance in Brucella suis (Zhang et al. 2021).

Bacteria
Pseudomonadota
BI-1 of Brucella suis
1.A.14.3.1









The NMDA receptor glutamate binding chain. Also called Protein lifeguard-1, putative MAPK-activating protein PMO2, and transmembrane BAX inhibitor motif-containing protein 3 (TMBIM3, GRINA, LFG1, NMDARA1). The human orthologue is Q7Z429.  Stimulation and block by spermine involve separate binding sites and distinct mechanisms (Jin et al. 2008).

Eukaryota
Metazoa, Chordata
NMDA receptor glutamate binding chain of Rattus sp. (Q63863)
1.A.14.3.2









Glutamate Receptor Gr2

Eukaryota
Gr2 of Capsaspora owczarzaki (E9CCY6)
1.A.14.3.3









Golgi anti-apoptotic protein, GAAP of 237 aas.  Forms cation-selective channels; residues that contribute to ion-conduction and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015).

Viruses
Bamfordvirae, Nucleocytoviricota
GAAP of Vaccinia virus, VacV (A2VCJ6)
1.A.14.3.4









Ionotropic glutamate receptor; N-methyl-D-aspartate-associated protein 1 (glutamate-binding).

Eukaryota
Metazoa, Chordata
Gr1 of Salmo salar (B5X2N0)
1.A.14.3.5









The BH3-only protein, Ynl205c (Büttner et al., 2011)

Eukaryota
Fungi, Ascomycota
Ynl305c of Saccharomyces cerevisiae (P48558)
1.A.14.3.6









Protein lifeguard 4 (LFG4), also called Golgi anti-apoptotic protein (GAAP), Protein S1R, CGI-119, Transmembrane BAX inhibitor motif-containing protein 4, (TMBIM4) and Z-protein.  Forms cation-selective ion channels. Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently of each other have been identified (Carrara et al. 2015).  It's functions have been reviewed (Carrara et al. 2017). The N-methyl-D-aspartate receptor regulates the circadian clock in megakaryocytic cells and impacts cell proliferation through BMAL1 (Hearn et al. 2023).

Eukaryota
Metazoa, Chordata
TMBIM4 of Homo sapiens
1.A.14.3.7









7 TMS integral membrane protein

Bacteria
Planctomycetota
Uncharacterized membrane protein of Rhodopirellula baltica
1.A.14.3.8









Uncharacterized protein of 242 aas and 7 TMSs.

Bacteria
Cyanobacteriota
UP of Synechococcus elongatus (Anacystis nidulans R2)
1.A.14.3.9









Lifeguard homologue, CG3814 of 244 aas and 7 TMSs.  Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons diminishes its neuroprotective ability, and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy (M'Angale and Staveley 2016).

Eukaryota
Metazoa, Arthropoda
CG3814 of Drosophila melanogaster (Fruit fly)
1.A.14.3.10









The Protein Lifeguard 3 (LFG3, RECS1, Tmbim1) of 311 aas and 7 TMSs. LFG3 is a multivesicular body regulator that protects against non-alcoholic fatty liver by targeting the lysosomal degradation of Tlr4 (Zhao et al. 2017). It also protects against pathological cardiac hypertrophy by promoting the lysosomal degradation of activated TLR4 (Deng et al. 2018). RECS1 is a pH-regulated calcium channel, an activity that is essential to trigger cell death (Pihán et al. 2021).

Eukaryota
Metazoa, Chordata
LFG3 of Homo sapiens
1.A.14.3.11









Uncharacterized protein of 638 aas and 7 N-terminal TMSs

Eukaryota
Metazoa, Arthropoda
UP of Drosophila eugracilis
1.A.14.3.12









Viroporin, pUS21, of 243 aas and 8 TMSs.  It modulates calcium ion homeostasis and protects cells against apoptosis (Luganini et al. 2018).  pUS21 of human cytomegalovirus (HCMV) constitutes a TMBIM-derived viroporin that may contribute to HCMV's overall strategy to counteract apoptosis of infected cells (Luganini et al. 2023).  US21, one of the 10 US12 genes (US12-US21), is a descendant of a captured cellular transmembrane BAX inhibitor motif-containing gene. It encodes a 7 TMS endoplasmic reticulum (ER)-resident viroporin (pUS21) capable of reducing the Ca2+ content of ER stores, which, in turn, protects cells against apoptosis. The US21 protein is a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity (Luganini et al. 2023).

Viruses
Heunggongvirae, Peploviricota
pUS21 of Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5)
1.A.14.3.13









Lifeguard 2, LFG2, or the Brz-insensitive-long hypocotyl4 mutant ,BIL4,  of 239 aas and 7 TMSs. BIL4 regulates cell elongation and Brassinosteroid (BRs; plant steroid hormones) signaling, in part  via the regulation of BRI1 localization (Yamagami et al. 2017).

 

Eukaryota
Viridiplantae, Streptophyta
BIL4 of Arabidopsis thaliana
1.A.14.3.14









GRINA  (Lifguard 1, LFG1, NMDARA1, TMBIM3) has 371 aas and 7 C-terminal TMSs.  It is expressed in 218 organ(s) with highest expression in the right hemisphere of the cerebellum.  It is involved in ER Ca2+ ion homeostasis and regulates apoptosis. The expression of the pro-apoptotic protein Bax is upregulated, whereas the anti-apoptotic protein Bcl-2 is downregulated in GRINA silenced cells (Xu et al. 2018).  Grina/TMBIM3 modulates NMDA receptors and voltage-gated CaV2.2 Ca2+ channels (TC# 1.A.1.11.9) in a G-protein-like manner (Mallmann et al. 2019). GRINA encodes the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif-containing protein family member 3), which regulates cell survival (Rice et al. 2019).

Eukaryota
Metazoa, Chordata
GRINA of Homo sapiens
1.A.14.3.15









Tmbim3a or Grinaa of 363 aas and 7 C-terminal TMSs. A deficiency in Tmbim3a/Grinaa initiates cold-induced ER stress and cell death by activating an intrinsic apoptotic pathway in zebrafish (Chen et al. 2019).

Eukaryota
Metazoa, Chordata
Grinaa of Danio rerio (Zebrafish) (Brachydanio rerio)
1.A.14.3.16









Protein lifeguard-2 (LFG, LFG2, NMP2, NMP35, TMBIM2), Fas-apoptotic inhibitory molecule 2 (FAIM2) is of 316 aas with 7 TMSs. It is an antiapoptotic protein which protects cells uniquely from Fas-induced apoptosis and regulates Fas-mediated apoptosis in neurons by interfering with caspase-8 activation (Somia et al. 1999; Fernández et al. 2007). It is a member of the transmembrane BAX inhibitor motif-containing (TMBIM) family. The TMBIM family is comprised of six anti-apoptotic proteins that suppress cell death by regulating endoplasmic reticulum Ca2+ homeostasis. It localizes to the lysosome and facilitates autophagosome-lysosome fusion through the LC3 interaction region (Hong et al. 2020). 

Eukaryota
Metazoa, Chordata
LFG2 of Homo sapiens
1.A.14.4.1









Viral protein HWLF3 (342 aas; 7 TMSs)

Viruses
Heunggongvirae, Peploviricota
HWLF3 of human cytomegalovirus, HHV-5 (Q03307)
1.A.14.4.2









Viral membrane protein US14 of 286 aas and 7 TMSs.

Viruses
Heunggongvirae, Peploviricota
US14 of Panine herpesvirus 2 (Chimpanzee cytomegalovirus)
1.A.14.4.3









Viral US18 protein of 274 aas and 7 TMSs

Viruses
Heunggongvirae, Peploviricota
US18 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5)
1.A.14.4.4









Membrane protein US12A of 250 aas and 7 TMSs

Viruses
Heunggongvirae, Peploviricota
US12A of Simian cytomegalovirus
1.A.14.4.5









Membrane protein US19 of 240 aas and 7 TMSs.

Viruses
Heunggongvirae, Peploviricota
US19 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5)