TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.A.112.1.1









Kidney metal (Mg2+) transporter, Cyclin (CNN) M2 isoform CRA_b (CNNM2). Defects cause hypomagnesemia. It has an extracellular N-terminus, an N-terminal TMS, a hydrophilic domain followed by 4 TMSs, another hydrophilic domain, and an intracellular C-terminus (de Baaij et al., 2012). CNNM2a forms heterodimers with the smaller isoform CNNM2b.  The human splice variant 1 of CNNM2 (ACDP2; Q9H8M5) is a Mg2+ transporter (Brandao et al. 2012).  The Bateman module is involved in AMP binding and Mg2+ sensing, and their binding causes a conformational change in the CBS module, transmitted to the transmembrane domain (Corral-Rodríguez et al. 2014).

Eukaryota
Metazoa
Cyclin M2, CNNM2, of Mus musculus (Q3TWN3)
1.A.112.1.2









Metal transporter CNNM3 (Ancient conserved domain-containing protein 3) (mACDP3) (Cyclin-M3) of 713 aas and probably 5 TMSs with one N-terminal, and four together in the first half of the protein (Chen et al. 2018). See the family description for the domain order of the CNNM proteins.

Eukaryota
Metazoa
CNNM3 of Mus musculus
1.A.112.1.3









Metal transporter CNNM3 (Ancient conserved domain-containing protein 3) (Cyclin-M3).  As of 2018, the function of this protein as a Mg2+ transporter is under debate (Schäffers et al. 2018).

Eukaryota
Metazoa
CNNM3 of Homo sapiens
1.A.112.1.4









Metal transporter CNNM4 (Ancient conserved domain-containing protein 4) (Cyclin-M4).  As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018).

Eukaryota
Metazoa
CNNM4 of Homo sapiens
1.A.112.1.5









Mg2+ exporter of 951 aas and 5 TMSs in a 1 + 4 TMS arrangement, CNNM1 (Chen et al. 2018).

Eukaryota
Metazoa
CNNM1 of Homo sapiens
1.A.112.1.6









Putative Mg2+ exporter of 875 aas and 5 TMSs, CNNM2 or ACDP2 (Chen et al. 2018). The bacterial CorC is involved in resistance to antibiotic exposure and to the survival of pathogenic microorganisms in their host environments. CorC possesses a cytoplasmic region containing the (regulatory ?) ATP-binding site (Huang et al. 2021). An inhibitor, IGN95a, targets the ATP-binding site and blocks both ATP binding and Mg2+ export. The cytoplasmic domain structure in complex with IGN95a was determined (Huang et al. 2021). With ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC shifts toward the inward-facing state of the transmembrane domain (Huang et al. 2021). These considerations suggest that CorC may be an ATP-driven Mg2+ efflux porter, and if so, the family belongs in TC sub-class, 3.A. CorC homologs may be able to export Mg2+, Co2+, Mn2+, Sr2+, Ba2+, Cu2+ and Fe2+.

Eukaryota
Opisthokonta
CNNM2 of Homo sapiens
1.A.112.1.7









Uncharacterized protein of 734 aas and 5 N-terminal TMSs.

Eukaryota
Kinetoplastida
UP of Trypanosoma cruzi
1.A.112.2.1









Uncharacterized protein of 384 aas and 4 TMSs.  The region of sequence similarity with established CorC proteins is in a hydrophilic region following the TMSs, putting into question the assignment of this protein to family 9.A.40. The N-terminal domain of 100 aas and 2 TMSs does not show sequence similarity with anything outside of the Candidatus Saccharibacteria bacteria.

Bacteria
Candidatus Saccharibacteria
UP of Candidatus Saccharibacteria bacterium
1.A.112.2.2









Uncharacterized protein of 434 aas with an N-terminal 4 TMSs, YrkA.

Bacteria
Firmicutes
YrkA of Bacillus subtilis (Q45494)
1.A.112.2.3









Probable Mg2+ exporter of 452 aas. It does not exhibit hemolysin activity (Sałamaszyńska-Guz and Klimuszko 2008).

Bacteria
Proteobacteria
TylC-like protein of Campylobacter jejuni
1.A.112.2.4









Uncharacterized protein of 444 aas and 4 TMSs, YhdP.  Mutations in yhdP increase the activity of sigmaW (Turner and Helmann 2000).

Bacteria
Firmicutes
YhdP of Bacillus subtilis
1.A.112.2.5









CorC homologue, YfjD or YpjE, of 428 aas and 4 TMSs in a 1 + 3 TMS arrangement at the N-terminus of the protein. This hydrophobic region is followed by a larger hydrophilic domain. It is encoded within a two gene operon with YpjD (CorE), a putative cytochrome c assembly protein of 8 or 9 TMSs (P64432; TC# 9.B.14.3.6) (Huang et al. 2021).

Bacteria
Proteobacteria
YfjD of E. coli
1.A.112.2.6









Uncharacterized CorC protein of 327 aas and 3 N-terminal TMSs.  The region of sequence similarity with  HlyC proteins (TC# 1.C.126) is in a hydrophilic C-terminal region following the TMSs.

Bacteria
Candidatus Saccharibacteria
UP of Candidatus Saccharibacteria bacterium
1.A.112.2.7









Mg2+ and Co2+ transporter, CorB, of 413 aas and 3 TMSs. It contains DUF21, CBS pair, and CorC-HlyC domainsin succession.

Bacteria
Proteobacteria
CorB of Pseudomonas bauzanensis
1.A.112.2.8









HlyC/CorC family transporter of 354 aas and 4 TMSs.

Bacteria
Actinobacteria
CorC domain protein of Micromonospora peucetia
1.A.112.2.9









Uncharacterized protein of 329 aas and 4 TMSs.

Bacteria
Verrucomicrobia
UP of Verrucomicrobia bacterium
1.A.112.2.10









Magnesium and cobalt efflux protein, CorC or MpfA (Magnesium Protection Factor A) of 449 aas and 4 N-terminal TMSs, apparently in a 2 + 2 TMS arrangement. Evidence has been presented that this protein catalyzes active Mg2+ extrusion from the cell (Armitano et al. 2016).  If so, It must be an active transporter, either a secondary carrier (TC subclass 2.A) or an ATP hydrolysis-driven exporter (TC subclass 3.A).

Bacteria
Firmicutes
MpfA of  Staphylococcus aureus
1.A.112.2.11









PaeA, YtfL, UPF0053 inner membrane protein, Duf21 domain containing protein, HlyC/CorC family transporter, hemolysin homolog of 447 aas and 4 N-terminal TMSs (residues 1 - 200) followed by a large hydrophilic domain (cystathionine beta-synthase, CBS, residues 201 - 447), possibly with a single TMS at about residue 320. It transports cadaverine and putrescine.  In fact, Salmonella, Klebsiella pneumoniae (TC# 1.A.112.1.12) and E. coli synthesize, import, and export cadaverine, putrescine, and spermidine to maintain physiological levels of polyamines and provide pH homeostasis. Both low and high intracellular levels of polyamines confer pleiotropic phenotypes or lethality. Iwadate et al. 2021 demonstrated that PaeA (YtfL) is required for reducing cytoplasmic cadaverine and putrescine concentrations. PaeA is involved in stationary phase survival when cells are grown in acidic medium in which they produce cadaverine. The paeA mutant is sensitive to putrescine, but not spermidine or spermine. Sensitivity to external cadaverine in stationary phase is only observed at pH > 8, suggesting that the polyamines need to be deprotonated to passively diffuse into the cell. In the absence of PaeA, intracellular polyamine levels increase and the cells lose viability. Ectopic expression of the known cadaverine exporter, CadB, in stationary phase partially suppresses the paeA mutant phenotype, and overexpression of paeA in exponential phase partially complements a cadB mutant grown in acidic medium. Thus, PaeA is a cadaverine/putrescine exporter, reducing potentially toxic levels under certain stress conditions (Iwadate et al. 2021).

Bacteria
Proteobacteria
PaeA of E. coli
1.A.112.2.12









YtfA, DUF21 domain-containing protein, HlyC/CorC family transporter, magnesium and cobalt efflux protein CorC_2 or CorC_3, of 445 aas and 4 N-terminal TMSs plus a large hydrophilic domain as the C-terminal 250 residues. Based on the E. coli ortholog, it probably transports putrescine and canavanine (Iwadate et al. 2021). Klebsiella pneumoniae is a source of widespread contamination of medical equipment, causing pneumonia as well as other multiorgan metastatic infections. During K. pneumoniae infections of lung epithelia, microtubules are severed and then eliminated, and YtfA plays a role, probably by secreting a relevant compound (Chua et al. 2019).

Bacteria
Proteobacteria
YtfL of Klebsiella pneumoniae