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Superfamily	Description
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.
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.
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.
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.
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.
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.
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.
Cecropin Superfamily	Tamang, D.G. and M.H. Saier, Jr. (2006). The cecropin superfamily of toxic peptides. J. Mol. Microbiol. Biotechnol. 11: 94-103.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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
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.
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. This superfamily may also include TC# 1.A.101 and 1.A.138.
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
Viral Envelope Fusion Protein (Env-FP) Superfamily	KeyNey
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.
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.
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.
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. Holin I Superfamily may be distantly related to Holin VI Superfamily.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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)]
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.
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).
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
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.
Copper Resistance (CuR) Superfamily
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.
O-Antigen Polymerase (OAPol) Superfamily
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.
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.
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.
Peroxisomal Peroxin/Unnexin (Pex/Unx) 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). They are distantly related to the Unnexin family (TC#1.A.138) as well. These two families may also belong to the Tetraspan Junctional Complex Superfamily, but this has not yet been established.
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.
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).
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).
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.
Adenylate/Guanylate Cyclase (A/GCyc) Superfamily	These enzymes catalyzed the synthesis of cAMP or cGMP from ATP or GTP, respectively.
Transmembrane Acyl Transferease (TmAT) Superfamily	These acyltransferases usually have 9 or 10 TMSs.
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.
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).
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.
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.
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.
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:
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.
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.
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.
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.
Retromer Superfamily	Retromer complexes function to recycle proteins including integral membrane proteins in various membrane, plasma and vacuolar membranes.
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.
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.
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).
YIP Superfamily	These proteins usually have 4 - 6 TMSs and function in intracellular protein trafficking in eukaryotes and as protein chaparone proteins in prokaryotes.
Membrane Fusion Pore (MFP) Superfamily	The proteins of the MFP superfamily are called hemagglutinins, Hemagglutinin-esterases (HE), fusion proteins, and fusion glycoproteins.
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.
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.
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.
Actinobacterial Outer Membrane Porin (A-OMP) Superfamily	The A-OMP superfamily consists of Actinobacterial proteins of about 500 aas with ~8 alpha helical TMSs.
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.
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.
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.
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.
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).
MACPF/TMPRSS/SelP-R Superfamily	The MACPF, TMPRSS and SelP-R 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, 3 families include members that are homologous to these proteins.
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.
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.
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. Several other TC families show sequence similarities (domains) with proteins in the following TC (multi-component) families: 1.F.1, 1.R.1, 3.A.16, 3.A.25, 3.A.28, 3.A.29, and 3.A.31.
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.
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.
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.
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.
Basigin-Tapasin-TREM2/PIGR Superfamily	This family includes seven 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 in TCDB, 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.
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).
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.
Gasdermin Superfamily	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.
Viroporin-1 Superfamily
Viroporin-2 Superfamily
Viroporin-3 Superfamily
Azolectin-Cytochrome c Pore-forming (ACCP) Superfamily	Cytochrome c in an Azolectin lipid bilayer creates ion-conducting pores.
Thiourea Artificial Ion Transporter Superfamily	Members of this superfamily include man-made molecules that transport ions via compounds containing thiourea.
Squaramide-containing Artifical Ion Transporter Superfamily	Members of this superfamily of man-made (artificial) compounds, all contain squaramide and transport anions, but one functions as a channel (1.D.197), and one functions as a carrier (2.B.88). Their inclusion in this superfamily is based on the presence of the same chemical group in the transporting compounds and not on protein phylogeny.
Crown Ether Artificial Ion Transporter Superfamily	Five families of man-made ion transporters, all functioning as transmembrane channels, contain crown-ethers. Their inclusion in this superfamily is based on the presence of the same chemical group in the transporting compounds and not on protein phylogeny.
Arene Artificial Ion Transporter (AAIT) Superfamily	Members of this superfamily contain Arenes and are man-made compounds that transport ions across membranes. Their inclusion in this superfamily is based on the presence of the same chemical group in the transporting compounds and not on protein phylogeny.
Calix[4]Pyrrole Superfamily	Calix[4]pyrroles are found in 3 TC families of anion carriers, TC#s 2.B.59, 2.B.73 and 2.B.111. Their inclusion in this superfamily is based on the presence of the same chemical group in the transporting compounds and not on protein phylogeny.
Triazole-containing Channel/Carrier Superfamily	Triazole-containing channel/carriers are man-made compounds that can transport ions across membranes. Three TC families currently comprise this superfamily. Their inclusion in this superfamily is based on the presence of the same chemical group in the transporting compounds and not on protein phylogeny.

Spanin Superfamily	Spanins are phage proteins that allow the final step of transport of proteins (i.e., endolysins) and small molecules together with holins across the bacterial cell membrane.
BMC Shell Protein Superfamily	Bacterial Micro/NanoCompartment Shell Protein Pores Bacterial Micro- or Nano-compartments fall into a class of proteinaceous 'organelles' or machines that serve a specific metabolic function (Saier 2013 [PMID 23920489]). The metabolic enzymes are sorrounded by 'shell' proteins, many of which are homologous and form oligomeric structures containing substrate selective pores through which substrates/products/intermediates can pass with differing permeabilities (Park et al. 2017 [PMID 28829618]). BMC shell constituents can be classified depending on their oligomerization state as hexamers (BMC-H), pentamers (BMC-P) or trimers (BMC-T) (Barthe L et al, 2023 [PMID 38011088]). Shell proteins may resemble viral capsid proteins and have a cellular orign (Krupovic & Koonin, 2017 [PMID 29132422]). BMCs are not found in archaea and eukaryotes (Ravcheev et al., 2019 [PMID: 31333721]).
Encapsulin Shell Protein (Enc) (of Bacterial/Archaeal Nanocompartments) Superfamily	This Enc superfamily consists of TC families 1.S.6 and 1.S.7. Encapsulin nanocontainers are versatile scaffolds for the development of artificial metabolons (Jenkins & Lutz, 2021 [33769792]).