TCDB is operated by the Saier Lab Bioinformatics Group

AAA-ATPase Superfamily

These ATPase are found as coomponents of several protein secretion systems as well as synaptosomal fusion systems. All of these systems are multi-component systems where the ATPases play energizing roles. See Miller JM, Enemark EJ., Fundamental Characteristics of AAA+ Protein Family Structure and Function. Archaea. 2016 PMID: 27703410.

1.F.1 - The Synaptosomal Vesicle Fusion Pore (SVF-Pore) Family
1.R.1 - The Membrane Contact Site (MCS) Family
3.A.16 - The Endoplasmic Reticular Retrotranslocon (ER-RT) Family
3.A.20 - The Peroxisomal Protein Importer (PPI) Family
3.A.24 - The Type VII or ESX Protein Secretion System (T7SS) Family
3.A.25 - The Symbiont-specific ERAD-like Machinery (SELMA) Family
3.A.28 - The AAA-ATPase, Bcs1 (Bcs1) Family
3.A.29 - The Mitochondrial Inner Membrane i-AAA Protease Complex (MIMP) Family
3.A.31 - The Endosomal Sorting Complexes Required for Transport III (ESCRT-III) Family

ABC1, ABC2, ABC3 Superfamilies

as well as the ECF sub-superfamily are all included within the functional ABC superfamily, TC#3.A.1. Their descriptions and constituent families are presented in paragraphs 3 and 4 of the superfamily description under TC#3.A.1. The ABC2 uptake Superfamily includes proteins in TC families 2.A.87 (P-RFT) and 2.A.88 (VUT or ECF).

For efflux systems see: (Wang, B., M. Dukarevich, E.I. Sun, M.R. Yen, and M.H. Saier, Jr. (2009). Membrane porters of ATP-binding cassette transport systems are polyphyletic. J. Membr. Biol. 231: 1-10.) for more details.

For uptake systems see: (Zheng, W.H., A. Västermark, M.A. Shlykov, V. Reddy, E.I. Sun, and M.H. Saier, Jr. (2013). Evolutionary relationships of ATP-Binding Cassette (ABC) uptake porters. BMC Microbiol 13: 98.) for more details.

2.A.87 - The Prokaryotic Riboflavin Transporter (P-RFT) Family
2.A.88 - The Vitamin Uptake Transporter (VUT) Family

Actinobacterial Outer Membrane Porin (A-OMP) Superfamily

The A-OMP superfamily consists of Actinobacterial proteins of about 500 aas with ~8 alpha helical TMSs.

1.B.89 - The Gordonia Outer Membrane Porin (GjpA) Family
1.B.94 - The Pro-Pro-Glu Outer Membrane Porin (PPE) Family
9.B.96 - The PE-PGRS Protein (PE-PGRS) Family

Adenylate/Guanylate Cyclase (A/GCyc) Superfamily

These enzymes catalyzed the synthesis of cAMP or cGMP from ATP or GTP, respectively.

8.A.59 - The SLC and TCST-Associated Component (STAC-A) Family
8.A.85 - The Guanylate Cyclase (GC) Family

Aerolysin Superfamily

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

1.C.3 - The α-Hemolysin Channel-forming Toxin (αHL) Family
1.C.4 - The Aerolysin Channel-forming Toxin (Aerolysin) Family
1.C.5 - The Channel-forming ε-toxin (ε-toxin) Family
1.C.13 - The Channel-forming Leukocidin Cytotoxin (Ctx) Family
1.C.14 - The Cytohemolysin (CHL) Family
1.C.43 - The Earthworm Lysenin Toxin (Lysenin) Family
1.C.74 - The Snake Cytotoxin (SCT) Family
1.C.78 - The Crystal Protein (Cry) Family
8.A.31 - The Ly-6 Neurotoxin-like Protein1 Precursor (Lynx1) Family
8.B.23 - The Mambalgin (Mambalgin) Family

Ankyrin Repeat Domain-containing (Ank) Superfamily

The Ankyrin Repeat Domain-containing (Ank) Superfamily is a domain found in at least some proteins in the following TC families:

1.I.1 - The Nuclear Pore Complex (NPC) Family
1.C.63 - The α-Latrotoxin (Latrotoxin) Family
1.A.105 - The Mixed Lineage Kinase Domain-like (MLKL) Family
1.C.104 - The Heterokaryon Incompatibility Prion/Amyloid Protein (HET-s) Family
3.A.5 - The General Secretory Pathway (Sec) Family
8.A.28 - The Ankyrin (Ankyrin) Family
8.A.35 - The Mycobacterial Membrane Protein Small (MmpS) Family
9.A.43 - The Cadmium Tolerance Efflux Pump (CTEP) Family

Anoctamin Superfamily

The Anoctamin superfamily is found under TC# 1.A.17 and contains 7 families. See PLoS One, 2018: e0192851. doi: 10.1371/journal.pone.0192851. eCollection 2018. Bioinformatic characterization of the Anoctamin Superfamily of Ca2+-activated ion channels and lipid scramblases. Medrano-Soto A, Moreno-Hagelsieb G, McLaughlin D, Ye ZS, Hendargo KJ, Saier MH Jr.

1.A.17 - The Calcium-dependent Chloride Channel (Ca-ClC) Family

APC Superfamily

The APC superfamily consists of numerous families of porters that transport amino acids and their dereivatives. See: Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81.

Wong, F.H., J.S. Chen, V. Reddy, J.L. Day, M.A. Shlykov, S.T. Wakabayashi, and M.H. Saier, Jr. (2012). The amino acid-polyamine-organocation superfamily. J. Mol. Microbiol. Biotechnol. 22: 105-113. These porters have the LeuT fold (Ferrada E and Superti-Furga G, 2022 [PMID 36164651]). These proteins have two 5 TMS repeats except for NCS2, AE and SulP which have two 7 TMS repeats. See: Vastermark A, Wollwage S, Houle ME, Rio R and Saier MH Jr. (2014). Expansion of the APC superfamily of secondary carriers, Proteins. 82:2797-2811. PMID: 25043943. and Västermark Å and Saier MH Jr. (2014) Evolutionary relationship between 5+5 and 7+7 inverted repeat folds within the amino acid-polyamine-organocation superfamily. Proteins. 82:336-46. PMID: 24038584.

2.A.3 - The Amino Acid-Polyamine-Organocation (APC) Family
2.A.15 - The Betaine/Carnitine/Choline Transporter (BCCT) Family
2.A.18 - The Amino Acid/Auxin Permease (AAAP) Family
2.A.21 - The Solute:Sodium Symporter (SSS) Family
2.A.22 - The Neurotransmitter:Sodium Symporter (NSS) Family
2.A.25 - The Alanine or Glycine:Cation Symporter (AGCS) Family
2.A.26 - The Branched Chain Amino Acid:Cation Symporter (LIVCS) Family
2.A.30 - The Cation-Chloride Cotransporter (CCC) Family
2.A.31 - The Anion Exchanger (AE) Family
2.A.39 - The Nucleobase:Cation Symporter-1 (NCS1) Family
2.A.40 - The Nucleobase/Ascorbate Transporter (NAT) or Nucleobase:Cation Symporter-2 (NCS2) Family
2.A.42 - The Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family
2.A.46 - The Benzoate:H+ Symporter (BenE) Family
2.A.53 - The Sulfate Permease (SulP) Family
2.A.55 - The Metal Ion (Mn2+-iron) Transporter (Nramp) Family
2.A.72 - The K+ Uptake Permease (KUP) Family
2.A.114 - The Putative Peptide Transporter Carbon Starvation CstA (CstA) Family
2.A.120 - The Proline/Amino Acid Permease (PAAP) Family

ArsA ATPase (ArsA) Superfamily

Includes ATPases in the following TC families: 2.A.59 (2.A.59.1.5 and 2.A.59.1.6 only), 3.A.4, 3.A.19 and 3.A.21. Castillo, R. and M.H. Saier. (2010). Functional Promiscuity of Homologues of the Bacterial ArsA ATPases. Int J Microbiol 2010: 187373. The ATPases of the ABC superfamily (TC# 3.A.1) may also be distantly related.

3.A.1 - The ATP-binding Cassette (ABC) Superfamily
3.A.4 - The Arsenite-Antimonite (ArsAB) Efflux Family
3.A.19 - The Guided Entry of Tail Anchored Protein (GET) Family
3.A.21 - The C-terminal Tail-Anchored Membrane Protein Biogenesis/ Insertion Complex (TAMP-B) Family

ATP-dependent Clp Protease (Clp) Superfamily

This superfamily includes proteins in at least three multi-component protein translocase systems in chloroplasts, Plasmodium and bacteria (TC#s 3.A.9, 3.A.23 and 3.A.26, respectively).

3.A.9 - The Chloroplast Envelope Protein Translocase (CEPT or Tic-Toc) Family
3.A.23 - The Type VI Symbiosis/Virulence Secretory System (T6SS) Family
3.A.26 - The Plasmodium Translocon of Exported proteins (PTEX) Family

Azolectin-Cytochrome c Pore-forming (ACCP) Superfamily

Cytochrome c in an Azolectin lipid bilayer creates ion-conducting pores.

1.A.132 - The Azolectin:Cytochrome C Pore (ACCP) Family
3.D.4 - The Proton-translocating Cytochrome Oxidase (COX) Superfamily

Bacterial Bacteriocin (BB) Superfamily

Hassan, M., M. Kjos, I.F. Nes, D.B. Diep, and F. Lotfipour. (2012). Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance. J Appl Microbiol 113: 723-736.

Nishie, M., J. Nagao, and K. Sonomoto. (2012). Antibacterial peptides (bacteriocins): an overview of their diverse characteristics and applications. Biocontrol Sci 17: 1-16. Ciumac D, Gong H, Hu X, Lu JR (2018). Membrane targeting cationic antimicrobial peptides. J Colloid Interface Sci 537: 163-185.

1.C.22 - The Lactococcin A (Lactococcin A) Family
1.C.24 - The Pediocin (Pediocin) Family
1.C.26 - The Lactacin X (Lactacin X) Family
1.C.27 - The Divergicin A (Divergicin A) Family
1.C.29 - The Plantaricin EF (Plantaricin EF) Family
1.C.30 - The Plantaricin JK (Plantaricin JK) Family
1.C.31 - The Channel-forming Colicin V (Colicin V) Family
1.C.53 - The Lactocyclicin Q (Lactocyclicin Q) Family
1.C.65 - The Type III Secretion System Plant Host Cell Membrane Pore-forming HrpF (HrpF) Family
1.C.102 - The Cerein (Cerein) Family

BART Superfamily

Mansour, N.M., Sawhney, M., Tamang, D.G., Vogl, C., Saier, M.H. Jr. 2007. The bile/arsenite/riboflavin transporter (BART) superfamily. FEBS Journal 274(3):612-29.

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

2.A.10 - The 2-Keto-3-Deoxygluconate Transporter (KdgT) Family
2.A.69 - The Auxin Efflux Carrier (AEC) Family
9.B.33 - The Sensor Histidine Kinase (SHK) Family
9.B.34 - The Kinase/Phosphatase/Cyclic-GMP Synthase/Cyclic di-GMP Hydrolase (KPSH) Family

Basigin-Tapasin-TREM2/PIGR Superfamily

This family includes six families including the Basigin Family (8.A.23), the Tapasin Family (8.A.196) and the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2/PIGR) Family (8.A.218). Homologs can also be found in the multi-component MHC II Receptor Complex (TC# 9.A.75) as well as the multi-component Invertebrate PMP22-Claudin (Claudin2) Family which includes 18 proteins, 4 or which belong to the BTT Superfamily. Most of these proteins have variable sizes (from 215 aas to 909 aas), two TMSs, N- and C-terminal and from 1 to 5 internal repeats of about 110 aas.

8.A.17 - The Na+ Channel Auxiliary Subunit β1-β4 (SCA-β) Family
8.A.23 - The Basigin (Basigin) Family
8.A.43 - The NEAT-domain containing methaemoglobin heme sequestration (N-MHS) Family
8.A.77 - The Sheddase (Sheddase) Family
8.A.196 - The Tapasin (Tapasin) Family
8.A.218 - The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Family

Bcl-2 Superfamily

The Bcl-2 Superfamily includes two families in TCDB, the Bcl-2 family (TC# 1.A.21), consisting of homologues, some of which form transmembrane pores, and the Bim Family (8.A.69), members of which influence apoptosis, either positively or negatively, and interact with TOM complex proteins (TC# 3.A.8).

1.A.21 - The Bcl-2 (Bcl-2) Family
8.A.69 - The Pro-apoptotic Bcl-2-Family Protein Bim (Bim) Family

Beta-Amyloid Protein-Protease Inhibitor Superfamily

This superfamily includes beta-amyloid proteins (TC# 1.C.50) and protease inhibitors (TC# 8.B.13) as well as a few additional proteins such as TC# 8.A.77.1.8 and TC# 9.B.87.1.17. Several members of this superfamily have internal repeat sequences of about 20-60 residues.

1.C.50 - The Amyloid β-Protein Peptide (AβPP) Family
8.B.13 - The Kunitz-type Serine Protease Inhibitor (HAI) Family

CAAX Superfamily

The CAAX Superfamily has been described: PMID: 21570408, Members of this family initially included proteases in families 1.A.54, 2.A.133, 3.A.11 and 3.A.15 and then was expanded with more distantly related families. All members of the families listed in this superfamily are peptidase, many of them being signal peptidases and prepilins.

8.A.150 - The Mitochondrial Metalloendopeptidase OMA1 (OMA1) Family
9.B.1 - The Integral Membrane CAAX Protease (CAAX Protease) Family
9.B.2 - The Integral Membrane CAAX Protease-2 (CAAX Protease2) Family
9.B.217 - The Transmembrane PrsW Protease (PrsW) Family
9.B.218 - The DUF2324 Family of Putative Integral Membrane Metaloproteases (IMMP) Family
9.B.220 - The CAAX Protease Self-Immunity (CAAX-PSI) Family
9.B.250 - The Uncharacterized Prokaryotic 5 TMS Protein-2 (UPP2) Family
9.B.252 - The Peptidase from Archaea and Bacteria-6 (PAB6) Family
9.B.291 - The Uncharacterized Prokaryotic Protein of 4 TMSs (UPP4) Family

Calmodulin/Calcineurin/KChIP (CaCa) Superfamily

This superfamily includes Calcium binding domains and proteins of about 220 aas. Many proteins in the Phox family (5.B.1) have N-terminal domains of about 220 aas that are homologous to the members of The Calmodulin Calcium Binding Protein (Calmodulin) Family (TC# 8.A.82) as well as the Mitochondrial EF Hand Ca2+ Uniporter Regulator (MICU) Family (TC# 8.A.44). Other proteins bearing this domain include Mitochondrial Carriers (TC# 2.A.29.23.1, 8 and 9) and the Programmed Cell Death 8 protein (O75340; TC# 3.A.5.9.1).

5.B.1 - The Phagocyte (gp91phox) NADPH Oxidase Family
8.A.44 - The Mitochondrial EF Hand Ca2+ Uniporter Regulator (MICU) Family
8.A.82 - The Calmodulin Calcium Binding Protein (Calmodulin) Family

Cation Diffusion Facilitator (CDF) Superfamily

Paulsen, I.T. and M.H. Saier, Jr. (1997). A novel family of ubiquitous heavy metal ion transport proteins. J. Membr. Biol. 156: 99-103.

Matias, M.G., K.M. Gomolplitinant, D.G. Tamang, and M.H. Saier, Jr. (2010). Animal Ca2+ release-activated Ca2+ (CRAC) channels appear to be homologous to and derived from the ubiquitous cation diffusion facilitators. BMC Res Notes 3: 158.

1.A.52 - The Ca2+ Release-activated Ca2+ (CRAC) Channel (CRAC-C) Family
2.A.4 - The Cation Diffusion Facilitator (CDF) Family
2.A.19 - The Ca2+:Cation Antiporter (CaCA) Family
2.A.103 - The Bacterial Murein Precursor Exporter (MPE) Family

Cecropin Superfamily

Tamang, D.G. and M.H. Saier, Jr. (2006). The cecropin superfamily of toxic peptides. J. Mol. Microbiol. Biotechnol. 11: 94-103.

1.C.17 - The Cecropin (Cecropin) Family
1.C.18 - The Melittin (Melittin) Family
1.C.32 - The Amphipathic Peptide Mastoparan (Mastoparan) Family
1.C.51 - The Pilosulin (Pilosulin) Family
1.C.52 - The Dermaseptin (Dermaseptin) Family
1.C.62 - The Pseudopleuronectes americanus (flounder) Pleurocidin (Pleurocidin) Family
1.C.76 - The Pore-forming Maculatin Peptide (Maculatin) Family
1.C.124 - The Antimicrobial Pore-forming Pandinin (Pin) Family

Circular Bacterial Bacteriocin (CBB) Superfamily

*1.C.53 is also shared with the BB Superfamily (see BB Superfamily list). Maqueda, M., M. Sánchez-Hidalgo, M. Fernández, M. Montalbán-López, E. Valdivia, and M. Martínez-Bueno. (2008). Genetic features of circular bacteriocins produced by Gram-positive bacteria. FEMS Microbiol. Rev. 32: 2-22.

1.C.28 - The Bacteriocin AS-48 Cyclic Polypeptide (Bacteriocin AS-48) Family
1.C.83 - The Gassericin (Gassericin) Family
1.C.84 - The Subtilosin (Subtilosin) Family
1.C.90 - The Carnocyclin A (Carnocyclin) Family

CNNM/HlyC Superfamily

The CNNM and HlyC families share a homologous domain which consists of the entirety of the HlyC proteins and the hydrophilic parts of the Cyclin M (CNNM) Family proteins. The transmembrane domain is only present in the CNNM family. The CNNM family proteins may be active transporters, but they are currently listed under Class 1.A. This homologous domain is also found in some members of the CLC Family (2.A.49), the TerC Family (TC# 2.A.109) and the Peptidase M50 Family (9.B.149). The hydrophilic domain in the CNNM family members may be capable of ATP binding and could be the energizer for transport. This would make sense since many of these proteins export cationic substrates.

1.A.112 - The Cyclin M Mg2+ Exporter (CNNM) Family
1.C.126 - The HlyC Haemolysin (HlyC) Family

Conotoxin Superfamily

Conotoxin precursors are numerous and divergent in sequence, but they usually have 60 - 120 aas with an N-terminal TMS. They are processed to the active toxin that targets a variety of channels and receptors (SD Robinson and RS Norton, Mar. Drugs 2014, 12, 6058-6101. This Superfamily may be related to the Defensin and Huwentoxin Superfamilies. Conotoxins (CnTX) are bioactive peptides produced by marine molluscs belonging to Conus genus. The structures of these venomous peptides are linked with disulfide bonds formed by a high degree of post-translational modifications and glycosylation steps which increase the diversity and rates of their evolution (A. Gallo et al, 2020 PMID 32877656). A historical perspective of Conotoxins targeting voltage-gated sodium channels has appeared (Groome, 2023, PMID 37103349).

8.B.4 - The Conotoxin T (Conotoxin T) Family
8.B.5 - The Na+/K+/Ca2+ Channel Targeting Tarantula Huwentoxin (THT) Family
8.B.6 - The Ca2+ Channel-targeting Spider Toxin (CST) Family
8.B.10 - The Psalmotoxin-1 (PcTx1) Family
8.B.16 - The Maurocalcine (MaCa) Family
8.B.20 - The Australian Scorpion Toxin (Liotoxin) Family
8.B.21 - The Spider Insecticidal Neurotoxin Cyrtautoxin (Cyrautoxin) Family
8.B.22 - The P-Conotoxin Cystine Knot (P-CCK) Family
8.B.28 - The Mu-Conotoxin (Mu-Conotoxin) Family
8.B.32 - The Nicotinic Acetylcholine Receptor-targeting Alpha-Conotoxin (A-Conotoxin) Family
8.B.34 - The Sigma-Conotoxin (Sigma-Conotoxin) Family
8.B.36 - The Contulakin Lt (Contulakin Lt) Family
8.B.40 - The Conotoxin Con-ikot-ikot/Conopressin/Conophysin/Conodipine (CCCCC) Family

Copper Resistance (CuR) Superfamily

9.A.55 - The TMEM205 (TMEM205) Family
9.B.62 - The Copper Resistance (CopD) Family

CPA Superfamily

Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81.

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

2.A.27 - The Glutamate:Na+ Symporter (ESS) Family
2.A.36 - The Monovalent Cation:Proton Antiporter-1 (CPA1) Family
2.A.37 - The Monovalent Cation:Proton Antiporter-2 (CPA2) Family
2.A.70 - The Malonate:Na+ Symporter (MSS) Family
2.A.81 - The Aspartate:Alanine Exchanger (AAEx) Family
2.A.98 - The Putative Sulfate Exporter (PSE) Family
3.B.1 - The Na+-transporting Carboxylic Acid Decarboxylase (NaT-DC) Family

Defensin Superfamily

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96. The Defensin SF may be distantly related to the Huwentoxin SF.

1.C.19 - The Defensin (Defensin) Family
1.C.45 - The Plant Defensin (Plant Defensin) Family
1.C.47 - The Insect/Fungal Defensin (Insect/Fungal Defensin) Family
1.C.85 - The Pore-Forming β-Defensin (β-Defensin) Family
8.B.1 - The Long (4C-C) Scorpion Toxin (L-ST) Superfamily
8.B.2 - The Short Scorpion Toxin (S-ST) Superfamily
8.B.7 - The Cl- Channel Peptide Inhibitor (GaTx1) Family
8.B.8 - The α-KTx15 scorpion toxin (α-KTx15) Family

Drug/Metabolite Transporter (DMT) Superfamily

2.A.7 (32 families)

Jack, D.L., N.M. Yang, and M.H. Saier, Jr. (2001). The drug/metabolite transporter superfamily. Eur J Biochem 268: 3620-3639.

Yen, M.R., J.S. Chen, J.L. Marquez, E.I. Sun, and M.H. Saier. (2010). Multidrug resistance: phylogenetic characterization of superfamilies of secondary carriers that include drug exporters. Methods Mol Biol 637: 47-64.

2.A.7 - The Drug/Metabolite Transporter (DMT) Superfamily

ENaC/P2X Superfamily

1.A.6 (ENaC) and 1.A.7 (P2X receptor) have similar 3-d structures and are likely to be homologous (Kawate et al, 2009; Gonzales et al, 2009)

Le, T. and M.H. Saier, Jr. (1997). Phylogenetic characterization of the epithelial Na+ channel (ENaC) family. Mol. Membr. Biol. 13: 149-157.

Gonzales, E.B., T. Kawate, and E. Gouaux. (2009). Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature 460: 599-604.

Kawate, T., J.C. Michel, W.T. Birdsong, and E. Gouaux. (2009). Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460: 592-598.

1.A.6 - The Epithelial Na+ Channel (ENaC) Family
1.A.7 - The ATP-gated P2X Receptor Cation Channel (P2X Receptor) Family

Endomembrane Protein-Translocon (EMPT) Superfamily

Several of the constituents of this superfamily are shared between families 3.A.16 and 3.A.25. Some of the other constituents are shared with other families (e.g., 1.C.105). Bolte, K., N. Gruenheit, G. Felsner, M.S. Sommer, U.G. Maier, and F. Hempel. (2011). Making new out of old: recycling and modification of an ancient protein translocation system during eukaryotic evolution. Mechanistic comparison and phylogenetic analysis of ERAD, SELMA and the peroxisomal importomer. Bioessays 33: 368-376.

G-protein-coupled receptor (GPCR)

This superfamily includes three families, all of which have at least 7 TMSs towards their C-termini. Several also have an N-terminal TMS. They include three TC families with TC#s 8.A.56, 9.A.14 and 9.B.14.

8.A.56 - The Wntless Protein (Wls) Family
9.A.14 - The G-protein-coupled receptor (GPCR) Family


Two families in TCDB include homologous gasdermins, those in eukaryotes (1.C.123) and those in prokaryotes (1.C.137). Both are very diverse in sequence.

1.C.123 - The Pore-forming Gasdermin (Gasdermin) Family
1.C.137 - The Bacterial Gasdermin (B-Gas) Family

Glycosyl Transferase/Transporter (GTT) Superfamily

Glycosyl transferases can be integral membrane proteins with numerous TMSs that in some cases have been shown to transport the growing polysaccharide chain as it is being elongated in a group translocation process.

4.D.1 - The Putative Vectorial Glycosyl Polymerization (VGP) Family
4.D.2 - The Glycosyl Transferase 2 (GT2) Family
4.D.3 - The Glycan Glucosyl Transferase (OpgH) Family

Glycosyl/Acyl Transferase (GAT) Superfamily

These integral membrane proteins vary in numbers of TMSs but usually have more than 8. They have been annotated as either acyl transferases or glycosyl transferases. This superfamily may included many TC families in section 9.B.

9.B.142 - The Integral membrane Glycosyltransferase family 39 (GT39) Family
9.B.144 - The DUF3367 (DUF3367) Family
9.B.183 - The Wzy Glycosyltransferase (EpsG) Family,
9.B.225 - The Mannosyl Transferase (MptB) Family
9.B.239 - The Uncharacterized Bacterial 10 - 13 TMS Protein (UBP2) Family
9.B.346 - The Uncharacterized Archaeal 4 or 6 TMS Protein (UA4,6P) Family

GTP-Binding Protein/GTPase (GTP-BP) Superfamily

The GTP-Binding Protein/GTPase Superfamily includes proteins from many multi-component transport systems, many of them involved in protein translocation. They include families 3.A.18, 3.A.30, 8.A.92, 9.A.3, 9.A.50, 9.A.60, and 9.A.63.

GTPase - Dynamin-like Mitochondrial Fusion/Fission (GTPase) Superfamily

The Dynamin-like GTPase Family includes proteins from many multi-component transport systems, some of them involved in organelle fusion and fission. They are found within TC families 1.I.1, 1.N.6, 1.R.1, 8.A.34 and 9.A.63.

Guided Entry of Tail-anchored Protein (GET) Superfamily

In Eukaryotes, tail-anchored proteins use a distinctive pathway for insertion. Animal systems are in TC# 3.A.19 while Fungal systems are in TC# 3.A.21. 3-D structural analyses suggest that the EMC family (TC# 3.A.27) is also a member of this superfamily as is the YidC family (TC# 2.A.9) (McDowell et al., 2020).

2.A.9 - The Membrane Protein Insertase (YidC/Alb3/Oxa1) Family
3.A.27 - The Endoplasmic Reticulum Membrane Protein Insertion Complex (EMC) Family

Holin I Superfamily

The three subfamilies of 1.E.11 are very distant from each other and therefore can be considered to be separate families. Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.11 - The φ11 Holin (φ11 Holin) Family

Holin II Superfamily

Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.1 - The P21 Holin S (P21 Holin) Family
1.E.6 - The T7 Holin (T7 Holin) Family
1.E.7 - The HP1 Holin (HP1 Holin) Family
1.E.25 - The Pseudomonas phage F116 Holin (F116 Holin) Family
1.E.50 - The Beta-Proteobacterial Holin (BP-Hol) Family

Holin III Superfamily

Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.2 - The λ Holin S (λ Holin) Family
1.E.3 - The P2 Holin (P2 Holin) Family
1.E.4 - The LydA Holin (LydA Holin) Family
1.E.5 - The PRD1 Phage P35 Holin (P35 Holin) Family
1.E.20 - The Pseudomonas aeruginosa Hol Holin (Hol Holin) Family
1.E.34 - The Putative Actinobacterial Holin-X (Hol-X) Family
1.E.41 - The Deinococcus/Thermus Holin (D/T-Hol) Family

Holin IV Superfamily

Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.10 - The Bacillus subtilis φ29 Holin (φ29 Holin) Family
1.E.16 - The Cph1 Holin (Cph1 Holin) Family
1.E.19 - The Clostridium difficile TcdE Holin (TcdE Holin) Family
1.E.40 - The Mycobacterial 4 TMS Phage Holin (MP4 Holin) Family
1.E.43 - The Putative Transglycosylase-associated Holin (T-A Hol) Family

Holin V Superfamily

Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.21 - The Listeria Phage A118 Holin (Hol118) Family
1.E.29 - The Holin Hol44 (Hol44) Family

Holin VI Superfamily

Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.12 - The φAdh Holin (φAdh Holin) Family
1.E.26 - The Holin LLH (Holin LLH) Family

Holin VII Superfamily

The family listed under TC# 1.E.36 consists of 6 subfamilies, several of which are distantly related. It can therefore be considered as a superfamily. Reddy, B.L. and M.H. Saier, Jr. (2013). Topological and phylogenetic analyses of bacterial holin families and superfamilies. Biochim. Biophys. Acta. 1828: 2654-2671.

1.E.36 - The Mycobacterial 2 TMS Phage Holin (M2 Hol) Family

Huwentoxin Superfamily

Diao, J., Lin, Y., Tang, J., and Liang, S. (2003). cDNA sequence analysis of seven peptide toxins from the spider Selenocosmia huwena. Toxicon 42: 715-723. The Huwentoxin SF may be distantly related to the Defensin SF.

8.B.3 - The Huwentoxin-1 (Huwentoxin-1) Family
8.B.12 - The Spider Toxin (STx2) Family
8.B.17 - The Sea Anemone Peptide Toxin Class III (ShI) Family
8.B.19 - The Sea Anemone K+ Channel Blocker Toxin, BcsTx3 (BcsTx3) Family

Hydrolase Superfamily

This superfamilly includes thioester hydrolases (Families 4.C.3 and 9.B.371) and proteases (8.A.51). These three families appear to be related although only distantly.

4.C.3 - The Acyl-CoA Thioesterase (ACoA-T) Family
8.A.51 - The Dipeptidyl-aminopeptidase-like Protein 6 beta subunit of Kv4 channels (DPP6) Family
9.B.371 - The PaaI Thioesterase (PTE) Family

Influenza A/B Virus M2 Protein (M2) Superfamily

The M2 proteins of Influenza types A and B are homologous in their transmembrane helices and share the active site channel motif: H(X3)W(X3)H.

1.A.19 - The Type A Influenza Virus Matrix-2 Channel (M2-C) Family
1.A.58 - The Type B Influenza Virus Matrix Protein 2 (BM2-C) Family

Iron-Sulfur Protein (ISP) Superfamily

Iron-Sulfur proteins are found within many multi-component electron carrier systems, several of which transport protons and/or electrons across the membrane.

3.D.6 - The Ion (H+ or Na+)-translocating NADH:Ferredoxin Oxidoreductase (NFO or RNF) Family
3.D.7 - The H2:Heterodisulfide Oxidoreductase (HHO) Family
3.D.8 - The Na+- or H+-Pumping Formyl Methanofuran Dehydrogenase (FMF-DH) Family
3.D.10 - The Prokaryotic Succinate Dehydrogenase (SDH) Family
3.D.11 - The Periplasmic Nitrate Reductase Complex (NAP) Complex Family
5.A.3 - The Prokaryotic Molybdopterin-containing Oxidoreductase (PMO) Family
5.B.4 - The Plant Photosystem I Supercomplex (PSI) Family
5.B.11 - The One Electron Transmembrane Transfer Complex (TmcABCD) Family
5.B.12 - The One Electron Transmembrane Transfer Complex (DsrMKJOP) Family
5.B.13 - The One Electron Transmembrane Transfer Complex (HmcABCDEF) Family

IT Superfamily

Prakash S, Cooper G, Singhi S, Saier MH. The ion transporter superfamily. Biochim Biophys Acta. 2003 Dec 3;1618(1):79-92.

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

2.A.8 - The Gluconate:H+ Symporter (GntP) Family
2.A.11 - The Citrate-Mg2+:H+ (CitM) Citrate-Ca2+:H+ (CitH) Symporter (CitMHS) Family
2.A.13 - The C4-Dicarboxylate Uptake (Dcu) Family
2.A.14 - The Lactate Permease (LctP) Family
2.A.28 - The Bile Acid:Na+ Symporter (BASS) Family
2.A.34 - The NhaB Na+:H+ Antiporter (NhaB) Family
2.A.35 - The NhaC Na+:H+ Antiporter (NhaC) Family
2.A.45 - The Arsenite-Antimonite (ArsB) Efflux Family
2.A.47 - The Divalent Anion:Na+ Symporter (DASS) Family
2.A.56 - The Tripartite ATP-independent Periplasmic Transporter (TRAP-T) Family
2.A.59 - The Arsenical Resistance-3 (ACR3) Family
2.A.61 - The C4-dicarboxylate Uptake C (DcuC) Family
2.A.62 - The NhaD Na+:H+ Antiporter (NhaD) Family
2.A.68 - The p-Aminobenzoyl-glutamate Transporter (AbgT) Family
2.A.94 - The Phosphate Permease (Pho1) Family
2.A.101 - The Malonate Uptake (MatC) Family (Formerly UIT1)
2.A.111 - The Na+/H+ Antiporter-E (NhaE) Family
2.A.118 - The Basic Amino Acid Antiporter (ArcD) Family

Lantibiotic Bacteriocin (La-Ba) Superfamily

The Lantibiotic Bacteriocin Superfamily consists of Class 1 (type1; TC# 1.C.21) and Class 2 (type 2; TC# 1.C.60) lantibiotic families.

1.C.21 - The Lacticin 481 (Lacticin 481) Family
1.C.60 - The Two-component Enterococcus faecalis Cytolysin (EFC) Family

Leucine-rich Repeat-containing Domain (LRRD) Superfamily

The Leucine-rich Repeat-containing Domain Family includes members that can be found in the following (sub)families/proteins: 1.A.5.1.1, 1.A.25.3, 1.A.87.2, 8.A.43.1, 9.A.5.1.1 and 9.A.14.1.5.

1.A.5 - The Polycystin Cation Channel (PCC) Family
1.A.25 - The Gap Junction-forming Innexin (Innexin) Family
1.A.87 - The Mechanosensitive Calcium Channel (MCA) Family

Lipase/Toxin Superfamily

The Lipase/Toxin Superfamily consists of proteins of various sizes and topologies from all types of organisms, the characterized members of which hydrolyze lipids such as triacylglycerides.

1.C.132 - The TseL Toxin (TseL) Family
8.A.178 - The Lipase Atg15 (Atg15) Family

LysE Superfamily

Tsu, Brian V.; Saier, Milton H. (2015). The LysE Superfamily of Transport Proteins Involved in Cell Physiology and Pathogenesis. PloS One 10 (10). doi:10.1371/journal.pone.0137184. ISSN 1932-6203. PMC 4608589. PMID 26474485. Vrljic M, Garg J, Bellmann A, Wachi S, Freudl R, Malecki MJ, Sahm H, Kozina VJ, Eggeling L, Saier MH Jr (1999). The LysE superfamily: topology of the lysine exporter LysE of Corynebacterium glutamicum, a paradyme for a novel superfamily of transmembrane solute translocators. J Mol Microbiol Biotechnol. 1999;1:327-36.

2.A.75 - The L-Lysine Exporter (LysE) Family
2.A.76 - The Resistance to Homoserine/Threonine (RhtB) Family
2.A.77 - The Cadmium Resistance (CadD) Family
2.A.95 - The 6 TMS Neutral Amino Acid Transporter (NAAT) Family
2.A.106 - The Ca2+:H+ Antiporter-2 (CaCA2) Family
2.A.107 - The MntP Mn2+ exporter (MntP) Family
2.A.108 - The Iron/Lead Transporter (ILT) Family
2.A.113 - The Nickel/cobalt Transporter (NicO) Family
2.A.116 - The Peptidoglycolipid Addressing Protein (GAP) Family
2.A.131 - The Aminobenzyl Carbon-arsenic Defining Exporter (ABCDE) Family
5.A.1 - The Disulfide Bond Oxidoreductase D (DsbD) Family
8.A.88 - The calciquestrin (CASQ) Family

MACPF Superfamily

The Membrane Attack Complex/Perforin Superfamily, G. Moreno-Hagelsieb, B. Vitug, A. Medrano-Soto, M. Saier, J Mol Microbiol Biotechnol. 2017;27(4):252-267.

1.C.12 - The Thiol-activated Cholesterol-dependent Cytolysin (CDC) Family

Major Facilitator (MFS) Superfamily

The Major Facilitator Superfamily (MFS) is the largest superfamily of secondary carriers known. It includes a few families of proteins that catalyze processes other than secondary transport. For example, evidence suggests that the Major Intrinsic Protein (MIP) family of aquaporins and glycerol channels is related to the MFS as are Rhomboid proteases and the glycosyl transferase (GT) superfamily. Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81. Reddy, V.S., M.A. Shlykov, R. Castillo, E.I. Sun, and M.H. Saier, Jr. (2012). The major facilitator superfamily (MFS) revisited. FEBS J. 279: 2022-2035. Wang et al., 2020, Expansion of the Major Facilitator Superfamily (MFS) to Include Novel Transporters as well as Transmembrane-Acting Enzymes, Biochmica Biophysica Acta, 1862, 18327, PMID 32205149.

2.A.1 - The Major Facilitator Superfamily (MFS)
2.A.2 - The Glycoside-Pentoside-Hexuronide (GPH):Cation Symporter Family
2.A.12 - The ATP:ADP Antiporter (AAA) Family
2.A.17 - The Proton-dependent Oligopeptide Transporter (POT/PTR) Family
2.A.48 - The Reduced Folate Carrier (RFC) Family
2.A.57 - The Equilibrative Nucleoside Transporter (ENT) Family
2.A.60 - The Organo Anion Transporter (OAT) Family
2.A.71 - The Folate-Biopterin Transporter (FBT) Family
2.A.85 - The Aromatic Acid Exporter (ArAE) Family
2.A.100 - The Ferroportin (Fpn) Family
2.A.125 - The Eukaryotic Riboflavin Transporter (E-RFT) Family
4.H.1 - The Lysyl Phosphatidylglycerol Synthase/Flippase (MprF) Family
5.B.2 - The Eukaryotic Cytochrome b561 (Cytb561) Family
9.B.57 - The Conidiation and Conidial Germination Protein (CCGP) Family
9.B.111 - The 6 TMS Lysyl tRNA Synthetase (LysS) Family
9.B.143 - The 6 TMS DUF1275/Pf06912 (DUF1275) Family

Major Intrinsic Protein (MIP) Superfamily

Reizer, J., A. Reizer, and M.H. Saier, Jr. (1993). The MIP family of integral membrane channel proteins: sequence comparisons, evolutionary relationships, reconstructed pathway of evolution, and proposed functional differentiation of the two repeated halves of the proteins. Crit. Rev. Biochem. Mol. Biol. 28: 235-257.

Park, J.H. and M.H. Saier, Jr. (1996). Phylogenetic characterization of the MIP family of transmembrane channel proteins. J. Membr. Biol. 153: 171-180.

1.A.8 - The Major Intrinsic Protein (MIP) Family
1.A.16 - The Formate-Nitrite Transporter (FNT) Family

Membrane Fusion Pore (MFP) Superfamily

The proteins of the MFP superfamily are called hemagglutinins, Hemagglutinin-esterases (HE), fusion proteins, and fusion glycoproteins.

1.G.1 - The Viral Pore-forming Membrane Fusion Protein-1 (VMFP1) Family
1.G.14 - The Influenza Virus Hemagglutinin/Fusion Pore-forming Protein (Influenza-H/FPP) Family

Mercuric Ion Pore (Mer) Superfamily

This family consists of 5 subfamilies, several of which are distantly related. Therefore it can be considered to be a superfamily. Ai Yamaguchi, Dorjee G. Tamang, Milton H Saier, Jr. (2007). Mercury Transport in Bacteria. Water, Air, and Soil Pollution. 182: 219 - 234.

Timothy Mok, JS. Chen, MA. Shlykov, MH. Saier Jr. (2012). Bioinformatic Analyses of Bacterial Mercury Ion (Hg2+) Transporters. Water, Air, and Soil Pollution. 223: 4445 - 4457.

1.A.72 - The Mercuric Ion Pore (Mer) Superfamily

Mitochondrial Carrier (MC) Superfamily

This superfamily includes 32 families, all listed under TC# 2.A.29).

Kuan, J. and M.H. Saier, Jr. (1993). The mitochondrial carrier family of transport proteins: structural, functional, and evolutionary relationships. Crit. Rev. Biochem. Mol. Biol. 28: 209-233.

Palmieri, F. and C.L. Pierri. (2010). Mitochondrial metabolite transport. Essays Biochem 47: 37-52.

Palmieri, F., C.L. Pierri, A. De Grassi, A. Nunes-Nesi, and A.R. Fernie. (2011). Evolution, structure and function of mitochondrial carriers: a review with new insights. Plant J. 66: 161-181.

2.A.29 - The Mitochondrial Carrier (MC) Family

Multidrug Resistance Protein, Na+ Transporting Mrp (Mrp) Superfamily

Mrp of Bacillus subtilis is a 7 subunit Na+/H+ antiporter complex (2.A.63.1.4). All subunits are homologous to the subunits in other members of this monovalent cation (K+ or Na+): proton antiporter-3 (CPA3) family as well as subunits in the archaeal hydrogenases (3.D.1.4.1 and 3.D.1.4.2) which share many subunits with NADH dehydrogenase subunits (3.D.1). The largest subunit of the Mrp complex (Mrp A and Mrp D) are homologous to the subunits in NADH dehydrogenases (NDH, ND2, ND4 and ND5 in the fungal NADH dehydrogenase complex) and most other NDHs. (TC#3.D.1) as well are subunits in the F420H2 dehydrogenase of Methanosarcina mazei (TC#3.D.9.1.1). (Zickermann et al. 2015). New subunits in three TC families are homologous, and in all such systems, these subunits may function as Na+/K+ and/or H+ transporters.

2.A.63 - The Monovalent Cation (K+ or Na+):Proton Antiporter-3 (CPA3) Family
3.D.1 - The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family
3.D.9 - The H+-translocating F420H2 Dehydrogenase (F420H2DH) Family

Multidrug/Oligosaccharidyl-lipid/Polysaccharide Flippase (MOP) Superfamily

This superfamily includes12 families, all listed under TC# 2.A.66.

Hvorup, R.N., B. Winnen, A.B. Chang, Y. Jiang, X.F. Zhou, and M.H. Saier, Jr. (2003). The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily. Eur J Biochem 270: 799-813.

Yen, M.R., J.S. Chen, J.L. Marquez, E.I. Sun, and M.H. Saier. (2010). Multidrug resistance: phylogenetic characterization of superfamilies of secondary carriers that include drug exporters. Methods Mol Biol 637: 47-64.

Shukla S, Baumgart T, (2020) Enzymatic trans-bilayer lipid transport: Mechanisms, efficiencies, slippage, and membrane curvature. Biochim Biophys Acta Biomembr. 2020 Dec 17;1863(3):183534. doi: 10.1016/j.bbamem.2020.183534. PMID: 33340491

2.A.66 - The Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily

MusI (MusI) Superfamily

The MusI superfamily includes 8 families, all listed under TC# 9.B.28. These proteins usually have 5, 6 or 7 TMSs, but their functions are unknown although postulated. MusI homologues may be auxiliary proteins of ABC systems. The MusI superfamily may include TC family 9.A.22, but this has not been proven.

9.A.22 - The Putative Bacillus Transporter or Unknown Function (BTUF) Family
9.B.28 - The Putative Essential Component of the MusEFGKI ABC Transporter, MusI (MusI) Family

NEAT/Basigin Chaparone (NBC) Superfamily

The NEAT and Basigin families are usually characterized by two TMSs, N- and C-terminal, where the N-terminal TMS is the leader sequence for secretion, and the C-terminal TMS is the membrane anchor. As indicated, 5 families include members that are homologous to these proteins.

1.C.39 - The Membrane Attack Complex/Perforin (MACPF) Family
8.A.131 - The Transmembrane Protease Serine 3 (TMPRSS3) Family
9.B.87 - The Selenoprotein P Receptor (SelP-Receptor) Family

O-Antigen Polymerase (OAPol) Superfamily

9.B.67 - The O-antigen Polymerase (OAP) Family
9.B.128 - The O-antigen Polymerase, WzyE (WzyE) Family

Outer Membrane Pore-forming Protein I (OMPP-I) Superfamily

The OMPP-I Superfamily is an exceptionally large superfamily including over 50 TC OMPP families. This conclusion is based on statistical analyses of primary sequence data (B. L. Reddy and M. H. Saier, Jr., PLOS One, DOI: 10.1371; journal.pone.0152733, April 11, 2016).

1.B.1 - The General Bacterial Porin (GBP) Family
1.B.2 - The Chlamydial Porin (CP) Family
1.B.3 - The Sugar Porin (SP) Family
1.B.4 - The Brucella-Rhizobium Porin (BRP) Family
1.B.5 - The Pseudomonas OprP Porin (POP) Family
1.B.6 - The OmpA-OmpF Porin (OOP) Family
1.B.7 - The Rhodobacter PorCa Porin (RPP) Family
1.B.8 - The Mitochondrial and Plastid Porin (MPP) Family
1.B.9 - The FadL Outer Membrane Protein (FadL) Family
1.B.10 - The Nucleoside-specific Channel-forming Outer Membrane Porin (Tsx) Family
1.B.11 - The Outer Membrane Fimbrial Usher Porin (FUP) Family
1.B.12 - The Autotransporter-1 (AT-1) Family
1.B.13 - The Alginate Export Porin (AEP) Family
1.B.14 - The Outer Membrane Receptor (OMR) Family
1.B.15 - The Raffinose Porin (RafY) Family
1.B.16 - The Short Chain Amide and Urea Porin (SAP) Family
1.B.17 - The Outer Membrane Factor (OMF) Family
1.B.18 - The Outer Membrane Auxiliary (OMA) Protein Family
1.B.19 - The Glucose-selective OprB Porin (OprB) Family
1.B.20 - The Two-Partner Secretion (TPS) Family
1.B.21 - The OmpG Porin (OmpG) Family
1.B.22 - The Outer Bacterial Membrane Secretin (Secretin) Family
1.B.23 - The Cyanobacterial Porin (CBP) Family
1.B.25 - The Outer Membrane Porin (Opr) Family
1.B.26 - The Cyclodextrin Porin (CDP) Family
1.B.31 - The Campylobacter jejuni Major Outer Membrane Porin (MomP) Family
1.B.32 - The Fusobacterial Outer Membrane Porin (FomP) Family
1.B.33 - The Outer Membrane Protein Insertion Porin (Bam Complex) (OmpIP) Family
1.B.35 - The Oligogalacturonate-specific Porin (KdgM) Family
1.B.39 - The Bacterial Porin, OmpW (OmpW) Family
1.B.42 - The Outer Membrane Lipopolysaccharide Export Porin (LPS-EP) Family
1.B.43 - The Coxiella Porin P1 (CPP1) Family
1.B.44 - The Probable Protein Translocating Porphyromonas gingivalis Porin (PorT) Family
1.B.49 - The Anaplasma P44 (A-P44) Porin Family
1.B.54 - The Intimin/Invasin (Int/Inv) or Autotransporter-3 (AT-3) Family
1.B.55 - The Poly Acetyl Glucosamine Porin (PgaA) Family
1.B.57 - The Legionella Major-Outer Membrane Protein (LM-OMP) Family
1.B.60 - The Omp50 Porin (Omp50 Porin) Family
1.B.61 - The Delta-Proteobacterial Porin (Delta-Porin) Family
1.B.62 - The Putative Bacterial Porin (PBP) Family
1.B.66 - The Putative Beta-Barrel Porin-2 (BBP2) Family
1.B.67 - The Putative Beta Barrel Porin-4 (BBP4) Family
1.B.68 - The Putative Beta Barrel Porin-5 (BBP5) Superfamily
1.B.70 - The Outer Membrane Channel (OMC) Family
1.B.71 - The Proteobacterial/Verrucomicrobial Porin (PVP) Family
1.B.72 - The Protochlamydial Outer Membrane Porin (PomS/T) Family
1.B.73 - The Capsule Biogenesis/Assembly (CBA) Family
1.B.78 - The DUF3374 Electron Transport-associated Porin (ETPorin) Family
1.B.80 - The Putative Trans-Outer Membrane Electron Flow Porin (TOM-EF) Family
1.B.81 - The DUF2490 Putative Beta Barrel Porin (DUF2490) Family
1.B.92 - The Proteobacterial Outer Membrane Porin, NilB (NilB) Family
1.B.95 - The Outer Membrane Protein YaiO (YaiO) Family
9.B.50 - The Outer Membrane Beta-barrel Endoprotease, Omptin (Omptin) Family
9.B.153 - The Putative Beta-Barrel Porin/Alpha Amylase or Phenol_MetA-deg (BBP/AA) Family
9.B.170 - The DUF3187 Putative Porin (DUF3187) Family
9.B.186 - The Putative Lipoprotein Suppressor of a ts bamD mutant, YiaD (YiaD) Family

Outer Membrane Pore-forming Protein II (OMPP-II) Superfamily

Niederweis, M. (2003). Mycobacterial porins--new channel proteins in unique outer membranes. Mol. Microbiol. 49: 1167-1177; B. L. Reddy and M. H. Saier, Jr., PLOS One, DOI: 10.1371; journal.pone.0152733, April 11, 2016

1.B.24 - The Mycobacterial Porin (MBP) Family
1.B.58 - The Nocardial Hetero-oligomeric Cell Wall Channel (NfpA/B) Family

Outer Membrane Pore-forming Protein III (OMPP-III) Superfamily

B. L. Reddy and M. H. Saier, Jr., PLOS One, DOI: 10.1371; journal.pone.0152733, April 11, 2016

1.B.28 - The Plastid Outer Envelope Porin of 24 kDa (OEP24) Family
1.B.47 - The Plastid Outer Envelope Porin of 37 kDa (OEP37) Family

Outer Membrane Pore-forming Protein IV (OMPP-IV) Superfamily

B. L. Reddy and M. H. Saier, Jr., PLOS One, DOI: 10.1371; journal.pone.0152733, April 11, 2016 This superfamily includes protein that comprise pores in multicomponent protein translocases as follows: 3.A.8 - [Tim17 (P39515) Tim22 (Q12328) Tim23 (P32897)]; 1.B.69 - [PXMP4 (Q9Y6I8) PMP24 (A2R8R0)]; 3.D.9 - [NDH 21.3 kDa component (P25710)]

1.B.30 - The Plastid Outer Envelope Porin of 16 kDa (OEP16) Family
1.B.69 - The Peroxysomal Membrane Porin 4 (PxMP4) Family
3.A.8 - The Mitochondrial Protein Translocase (MPT) Family

Outer Membrane Pore-forming Protein V (OMPP-V) Superfamily

Rath, P., O. Saurel, M. Tropis, M. Daffé, P. Demange, and A. Milon. (2013). NMR localization of the O-mycoloylation on PorH, a channel forming peptide from Corynebacterium glutamicum. FEBS Lett. 587: 3687-3691. B. L. Reddy and M. H. Saier, Jr., PLOS One, DOI: 10.1371; journal.pone.0152733, April 11, 2016

1.B.34 - The Corynebacterial Porin A (PorA) Family
1.B.59 - The Outer Membrane Porin, PorH (PorH) Family

P-type ATPase (P-ATPase) Superfamily

Seventeen families of P-type ATPases are present under TC# 3.A.3.

Thever, M.D. and M.H. Saier, Jr. (2009). Bioinformatic characterization of p-type ATPases encoded within the fully sequenced genomes of 26 eukaryotes. J. Membr. Biol. 229: 115-130.

Chan, H., V. Babayan, E. Blyumin, C. Gandhi, K. Hak, D. Harake, K. Kumar, P. Lee, T.T. Li, H.Y. Liu, T.C. Lo, C.J. Meyer, S. Stanford, K.S. Zamora, and M.H. Saier, Jr. (2010). The p-type ATPase superfamily. J. Mol. Microbiol. Biotechnol. 19: 5-104.

3.A.3 - The P-type ATPase (P-ATPase) Superfamily

Peroxisomal Peroxin (Pex) Superfamily

Pex11 of yeast has been shown to be a pore-forming protein (see TC# 1.A.101 which contains 8 families). It is homologous and similar in size to Pex25 and Pex27. All three proteins are constituents of the Peroxisomal Protein Importer (PPI) Family (see TC# 3.A.20.1.2, 4 and 5).

1.A.101 - The Peroxisomal Pore-forming Pex11 (Pex11) Family

Phage Portal Protein (PPP) Superfamily

Phage portal proteins are found in phage, bacteria and archaea, and are usually about 500 aas +/-100 aas, but smaller and larger members are known. The 3-D structures of several have been solved, and these proteins all have the same fold.

1.W.1 - The Phage Portal Protein 1 (PPP1) Family
1.W.2 - The Phage Portal Protein 2 (PPP2) Family
1.W.3 - The Phage Portal Protein 3 (PPP3) Family
1.W.5 - The (Lambda) Phage Portal Protein 5 (PPP5) Family
1.W.7 - The (Bacillus Phage SPP1) Portal Protein 7 (PPP7) Family
1.W.8 - The (Enterobacterial phage T4) Portal Protein 8 (PPP8) Family
1.W.9 - The Escherichia coli Mu Phage Portal Protein 9 (PPP9) Family
1.W.10 - The (Enterobacterial Phage T7) Portal Protein 10 (PPP10) Family

Phospholemman/SIMP/Viroporin (PSV) Superfamily

The members of this superfamily are small proteins with a single TMS, although in a few members this TMS is internally duplicated to give 2 TMS proteins. They function as channels and auxiliary transport proteins.

1.A.27 - The Phospholemman (PLM) Family
1.A.95 - The Ephemerovirus Viroporin (EVVP) Family
1.A.100 - The Rhabdoviridae Putative Viroporin, U5 (RV-U5) Family
1.A.113 - The Small Integral Membrane Protein (SIMP) Family

Phospholipid Transporter/Phosphatase (PL-TP) Superfamily

The PL-TP superfamily consists of proteins with N-terminal integral membrane transporter domains and C-terminal hydrophilic phosphatase domains. The cardiolipin transporter (TC# 2.A.127.1.1) is the best characterized member of the superfamily.

2.A.127 - The Enterobacterial Cardiolipin Transporter (CLT) Family
9.B.105 - The Lead Resistance Fusion Protein (PbrBC) Family

Pleurotolysin Superfamily

The Pleurotolysin Superfamily consists of two closely related overlapping families, 1.C.97 and 1.C.119. Several well characterized pore-forming toxins are included in these two families.

1.C.97 - The Pleurotolysin Pore-forming (Pleurotolysin) Family
1.C.119 - The Aegerolysin (Aegerolysin) Family

Polyphosphate Polymerase/YidH (PoPo) Superfamily

Full length polyphosphate polymerases (TC# 4.E.1) have a C-terminal 3 TMS domain that is in the ubiquitous DUF202 domain/E. coli YidH protein Family (TC# 9.B.51). These small proteins, all with 3 TMSs, are found in bacteria, archaea and eukaryotes.

4.E.1 - The Vacuolar (Acidocalcisome) Polyphosphate Polymerase (V-PPP) Family
9.B.51 - The Uncharacterized DUF202/YidH (YidH) Family

Pore-forming Cytotoxin (PfCTx) Superfamily

The PfCTx superfamily consists of proteins, most of them large (between about 500 - 5000 aas), made by a wide range of organisms (a wide range of bacteria and eukaryotes). Family 1.C.41 show very limited sequence similarity with family 1.C.36, of 3 and 5 distantly related families, respectively, and they could be related, but this has not been demonstrated.

1.C.41 - The Tripartite Haemolysin BL (HBL) Family

Protease Inhibitor-like (PI-l) Superfamily

Different families within this superfamilies appear to have different modes of action, and indeed they are not homologous throughout their lengths. However they do show sequence similarity in at least one internal domain.

8.A.180 - The Retinol-binding protein (RBP) Family

Protein Kinase (PK) Superfamily

Protein kinase domains are sometimes found in transport proteins. These include TC#s 1.A.87.2.1-6, 1.A.105.1.1, 1.C.104.2.4, 1.C.127.1.7 1.E.43.3.3, 1.I.1.1.3 (with four such proteins in this system), 8.A.23.1.7, 8.A.24.1.11, 8.A.104.1., 8.A.105.1.1, 9.A.15.1.1, 9.B.45.1.3, 9.B.106.3.1-3, and 9.B.321.1.1. Some of these proteins have channel/transport domains distinct from the kinase domains.

8.A.104 - The 5'-AMP-activated protein kinase (AMPK) Family
9.A.15 - The Autophagy-related Phagophore-formation Transporter (APT) Family
9.B.106 - The Pock Size-determining Protein (PSDP) Family

PTS-AG Superfamily

Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81.

4.A.5 - The PTS Galactitol (Gat) Family
4.A.7 - The PTS L-Ascorbate (L-Asc) Family

PTS-GFL Superfamily

Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81.

Nguyen T.X., Yen M.R., Barabote R.D., Saier M.H. Jr. 2006. Topological predictions for integral membrane permeases of the phosphoenolpyruvate:sugar phosphotransferase system. J Mol Microbiol Biotechnol. 11(6):345-60.

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

4.A.1 - The PTS Glucose-Glucoside (Glc) Family
4.A.2 - The PTS Fructose-Mannitol (Fru) Family
4.A.3 - The PTS Lactose-N,N'-Diacetylchitobiose-β-glucoside (Lac) Family
4.A.4 - The PTS Glucitol (Gut) Family

Putative MusI Hydrolase (MusI) Superfamily

Most members of the MusI Superfamily belong to TC families 9.A.22 and 9.B.28, having 5 or 6 TMSs. Most are hypothetical proteins, but some are annotated as various hydrolases.

Resistance-Nodulation-Cell Division (RND) Superfamily

9 families are listed under TC# 2.A.6. (see Tseng, T.T., K.S. Gratwick, J. Kollman, D. Park, D.H. Nies, A. Goffeau, and M.H. Saier, Jr. (1999). The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1: 107-125.

Yen, M.R., J.S. Chen, J.L. Marquez, E.I. Sun, and M.H. Saier. (2010). Multidrug resistance: phylogenetic characterization of superfamilies of secondary carriers that include drug exporters. Methods Mol Biol 637: 47-64.

2.A.6 - The Resistance-Nodulation-Cell Division (RND) Superfamily

Retromer Superfamily

Retromer complexes function to recycle proteins including integral membrane proteins in various membrane, plasma and vacuolar membranes.

8.A.194 - The Sorting Nexin (SNX) Family
9.A.3 - The Sorting Nexin27 (SNX27)-Retromer Assembly Apparatus (RetromerAA) Family
9.A.63 - The Retromer-dependent Vacuolar Protein Sorting (R-VPS) Family

RTX-toxin Superfamily

Chen, J.S., V. Reddy, J.H. Chen, M.A. Shlykov, W.H. Zheng, J. Cho, M.R. Yen, and M.H. Saier, Jr. (2011). Phylogenetic characterization of transport protein superfamilies: superiority of SuperfamilyTree programs over those based on multiple alignments. J. Mol. Microbiol. Biotechnol. 21: 83-96.

1.C.11 - The Pore-forming RTX Toxin (RTX-toxin) Family
1.C.56 - The Pseudomonas syringae HrpZ Target Host Cell Membrane Cation Channel (HrpZ) Family
1.C.57 - The Clostridial Cytotoxin (CCT) Family
1.C.105 - The Bacillus thuringiensis Vegetative Insecticidal Protein-3 (Vip3) Family

Stomatin/Erlin/Podicin Superfamily

This super-family includes two families in TCDB, 8.A.21 and 8.A.195 as well as one member each from families 1.A.6 (member 1.A.6.2.2, where the erlin protein domain is within a subunit of the system), and 1.P.1 (member 1.P.1.1.1, where the erlin proteins are subunits of the system).

8.A.21 - The Stomatin/Podocin/Band 7/Nephrosis.2/SPFH (Stomatin) Family
8.A.195 - The Erlin1/2 Complex (Erlin) Family

Synaptotagmin Domain-containing (SynapD) Superfamily

Several proteins in TCDB contain one or two ~100 aa synaptotagmin domains that are involved in calcium and receptor signalling as well as intracellular lipid transport (Pinheiro et al., 2016; PMID# 27731902).

8.A.30 - The Nedd4-Family Interacting Protein-2 (Nedd4) Family
8.A.78 - The Insulin Secretion-regulating Lipid Transporter TMEM24 (TMEM24) Family
9.A.48 - The Unconventional Protein Secretion (UPS) System Family
9.A.57 - The Extended-Synaptotagmin (E-Syt) Family

Tetraspan Junctional Complex Protein or MARVEL (4JC) Superfamily

Hua, V.B., A.B. Chang, J.H. Tchieu, N.M. Kumar, P.A. Nielsen, and M.H. Saier, Jr. (2003). Sequence and phylogenetic analyses of 4 TMS junctional proteins of animals: connexins, innexins, claudins and occludins. J. Membr. Biol. 194: 59-76; Attwood MM, Krishnan A, Pivotti V, Yazdi S, Almen MS, Schioth HB. Topology based identification and comprehensive classification of four-transmembrane helixcontaining proteins (4TMs) in the human genome. BMC Genomics. 2016 PMID: 27030248; Chou A, Lee A, Hendargo KJ, Reddy VS, Shlykov MA, Kuppusamykrishnan H, Medrano-Soto A, Saier MH Jr. (2017). Characterization of the tetraspan junctional complex (4JC) superfamily. Biochim Biophys Acta. 2017 Mar;1859(3):402-414. PMID 27916633.

1.H.1 - The Claudin Tight Junction (Claudin1) Family
1.H.2 - The Invertebrate PMP22-Claudin (Claudin2) Family
1.A.24 - The Gap Junction-forming Connexin (Connexin) Family
1.A.36 - The Intracellular Chloride Channel (ICC) Family
1.A.64 - The Plasmolipin (Plasmolipin) Family
1.A.81 - The Low Affinity Ca2+ Channel (LACC) Family
1.A.82 - The LHFPL Tetraspan Protein (LTSP) Family
1.A.84 - The Calcium Homeostasis Modulator Ca2+ Channel (CALHM-C) Family
8.A.16 - The Ca+ Channel Auxiliary Subunit γ1-γ8 (CCAγ) Family
9.A.27 - The Non-Classical Protein Exporter (NCPE) Family
9.A.46 - The Clarin (CLRN) Family
9.B.41 - The Occludin (Occludin) Family
9.B.130 - The Tetraspan Vesicle Membrane Protein (TVP) Family
9.B.179 - The MscS/DUF475 (DUF475) Family

Toxin/Amyloid/Protease Inhibitor (TAPI) Superfamily

The TAPI Superfamily consists of large native proteins of several hundred residues as well as small proteolytically processed proteins of about 60 - 120 residues. In the shorter proteins, the same region of the large proteins is the active species.

Transmembrane Acyl Transferease (TmAT) Superfamily

These acyltransferases usually have 9 or 10 TMSs.

9.B.97 - The Acyltransferase-3/Putative Acetyl-CoA Transporter (ATAT) Family
9.B.169 - The Integral Membrane Protein (8 -10 TMSs) YeiB or DUF418 (YeiB) Family

Transmembrane One Electron Transfer Cytochrome (TM-Cyt) Superfamily

The multi-component families listed under this superfamily share several constituents, and all are included in subfamily 5.B. However, two other families, 5.A.3 and 3.D.7, contain constituents that are homologous to some of these proteins.

5.B.3 - The Geobacter Nanowire Electron Transfer (G-NET) Family
5.B.5 - The Extracellular Metal Oxido-Reductase (EMOR) Family
5.B.8 - The Trans-Outer Membrane Electron Transfer Porin/Cytochrome Complex (ET-PCC) Family

Transporter-Opsin-G protein-coupled receptor (TOG) Superfamily

Yee, D.C., M.A. Shlykov, A. Västermark, V.S. Reddy, S. Arora, E.I. Sun, and M.H. Saier, Jr. (2013). The transporter-opsin-G protein-coupled receptor (TOG) superfamily. FEBS J. 280: 5780-5800.

2.A.43 - The Lysosomal Cystine Transporter (LCT) Family
2.A.52 - The Ni2+-Co2+ Transporter (NiCoT) Family
2.A.82 - The Organic Solute Transporter (OST) Family
2.A.102 - The 4-Toluene Sulfonate Uptake Permease (TSUP) Family
2.A.104 - The L-Alanine Exporter (AlaE) Family
2.A.119 - The Organo-Arsenical Exporter (ArsP) Family
2.A.123 - The Sweet; PQ-loop; Saliva; MtN3 (Sweet) Family
2.A.129 - The Lipid-linked Sugar Translocase (LST) Family
3.E.1 - The Ion-translocating Microbial Rhodopsin (MR) Family
3.E.3 - The HelioRhodopsin (HelioR) Family
9.B.191 - The Endoplasmic Reticulum Retention Receptor (KDELR) Family

Ubiquitin Ligase (UL) Superfamily

These proteins are listed either under TC subclass 8.A or within ERAD families as a component of families 3.A.16 or 3.A.20. Other TC families may be homologous but more distant.

8.A.112 - The Respiratory Supercomplex Factor (Rcf) Family
8.A.183 - The RelA-associated Inhibitor (RAI) Family

Urea Transporter/Na+ Exporter (UT/RnfD/NqrB) Superfamily

The Na+ pumping NQR (3.D.5) and RNF (3.D.6) families include protein complexes of six homologous but dissimilar subunits. Two of the six subunits, NqrD and NqrE, and RnfA and RnfD are homologous to each other. However, within 3.D.5 and 3.D.6, only one of the six protein constituents, NqrB and RnfD, respectively, is homologous to Urea Transporters (UT, 1.A.28), and these are believed to be responsible for Na+ transport.

1.A.28 - The Urea Transporter (UT) Family
3.D.5 - The Na+-translocating NADH:Quinone Dehydrogenase (Na-NDH or NQR) Family

Vesicle-associated Membrane Protein (VAMP) Superfamily

These proteins are integral membrane proteins that are associated with intracellular vesicles in eukaryotes. They regulate lipid transport and homeostasis, membrane trafficking, neurotransmitter release, stabilization of presynaptic microtubules, and the unfolded protein response.

8.A.119 - The Potassium Channel Regulatory Protein Sup-10 (Sup-10) Family
9.B.17 - The VAMP-associated protein (VAP) Family

VIC Superfamily

Chang A.B., Lin R., Studley W.K., Tran C.V., Saier M.H. Jr. 2004. Phylogeny as a Guide to Structure and Function of Membrane Transport Proteins. Mol Membr Biol. 21(3):171-81.

1.A.1 - The Voltage-gated Ion Channel (VIC) Superfamily
1.A.2 - The Inward Rectifier K+ Channel (IRK-C) Family
1.A.3 - The Ryanodine-Inositol 1,4,5-triphosphate Receptor Ca2+ Channel (RIR-CaC) Family
1.A.4 - The Transient Receptor Potential Ca2+/Cation Channel (TRP-CC) Family
1.A.10 - The Glutamate-gated Ion Channel (GIC) Family of Neurotransmitter Receptors
1.A.51 - The Voltage-gated Proton Channel (VPC) Family
2.A.38 - The K+ Transporter (Trk) Family

Viral Envelope Fusion Protein (Env-FP) Superfamily


1.G.2 - The Viral Pore-forming Membrane Fusion Protein-2 (VMFP2) Family
1.G.9 - The Syncytin (Syncytin) Family
1.G.12 - The Avian Leukosis Virus gp95 Fusion Protein (ALV-gp95) Family
1.G.18 - The SARS-CoV Fusion Peptide in the Spike Glycoprotein Precursor (SARS-FP) Family


1.A.92 - The Reovirus Viroporin VP10 (RVP10) Family
1.A.93 - The Bluetongue Virus Non-Structural Protein 3 Viroporin (NS3) Family
1.A.94 - The Rotavirus Non-structural Glycoprotein 4 Viroporin (NSP4) Family


1.A.57 - The Human SARS Coronavirus Viroporin (SARS-VP) Family
1.A.117 - The Coronavirus Membrane Matrix-Protein (M-Protein) Family


1.A.65 - The Coronavirus Viroporin E Protein (Viroporin E) Family
1.A.99 - The Infectious Bronchitis Virus Envelope Small Membrane Protein E (IBV-E) Family
1.A.116 - The Pore-forming Porcine Reproductive and Respiratory Syndrome Virus Viroporin (PRRSV) Family

YIP Superfamily

These proteins usually have 4 - 6 TMSs and function in intracellular protein trafficking in eukaryotes and as protein chaparone proteins in prokaryotes.

9.B.29 - The 4-5 TMS Putative Chaperone (4-5PC) Family
9.B.135 - The Membrane Trafficking Yip (Yip) Family