APC superfamily

Identifiers
Symbol	APC
Pfam clan	CL0062
ECOD	5051.1.1
TCDB	2.A.3
OPM superfamily	64

Last updated August 01, 2024

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known,^[1] and it contains several Solute carriers.^[2]^[3] Originally, the APC superfamily consisted of subfamilies under the transporter classification number (TC # 2.A.3). This superfamily has since been expanded to include eighteen different families.

The most recent families added include the PAAP (Putative Amino Acid Permease), LIVCS (Branched Chain Amino Acid:Cation Symporter), NRAMP (Natural Resistance-Associated Macrophage Protein), CstA (Carbon starvation A protein), KUP (K⁺ Uptake Permease), BenE (Benzoate:H⁺ Virginia Symporter), and AE (Anion Exchanger). Bioinformatic and phylogenetic analysis is used to continually expand currently existing families and superfamilies.

Other constituents of the APC superfamily are the AAAP family (TC# 2.A.18), the HAAAP family (TC# 2.A.42) and the LCT family (TC# 2.A.43). Some of these proteins exhibit 11 TMSs. Eukaryotic members of this superfamily have been reviewed by Wipf et al. (2002) ^[4] and Fischer et al. (1998).^[5]^[6]

Families

Currently recognized families within the APC Superfamily (with TC numbers in blue) include:^[6]

APC proteins in humans

There are several APC proteins expressed in humans, and they are SLC proteins.^[3]^[7]^[2] There are 11 SLC families including APC proteins: SLC4, 5, 6, 7, 11, 12, 23, 26, 32, 36, and 38.^[3] The atypical SLC TMEM104 is also clustered to the APC clan.^[3]

Structure and function

The topology of the well-characterized human Anion Exchanger 1 (AE1) conforms to a UraA-like topology of 14 TMSs (12 α-helical TMSs and 2 mixed coil/helical TMSs). All functionally characterized members of the APC superfamily use cation symport for substrate accumulation except for some members of the AE family which frequently use anion:anion exchange. All new entries contain the two 5 or 7 TMS repeat units characteristic of the APC superfamily, sometimes with extra TMSs at the ends likely the result of an addition prior to duplication. The CstA family contains the greatest variation in TMSs. New functionally characterized members transport amino acids, peptides, and inorganic anions or cations. Except for anions, these are typical substrates of established APC superfamily members. Active site TMSs are rich in glycyl residues in variable but conserved arrangements.

In CadB of E. coli (2.A.3.2.2), amino acid residues involved in both uptake and excretion, or solely in excretion are located in the cytoplasmic loops and the cytoplasmic side of transmembrane segments, whereas residues involved in uptake are located in the periplasmic loops and the transmembrane segments.^[8] A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII.^[8] Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "rocking bundle" mechanism.^[6]^[9]^[10]

The structure and function of the cadaverine-lysine antiporter, CadB (2.A.3.2.2), and the putrescine-ornithine antiporter, PotE (2.A.3.2.1), in E. coli have been evaluated using model structures based on the crystal structure of AdiC (2.A.3.2.5), an agmatine-arginine antiporter ( PDB: 3L1L ). The central cavity of CadB, containing the substrate-binding site is wider than that of PotE, mirroring the different sizes of cadaverine and putrescine. The size of the central cavity of CadB and PotE is dependent on the angle of transmembrane helix 6 (TM6) against the periplasm. Tyr(73), Tyr(89), Tyr(90), Glu(204), Tyr(235), Asp(303), and Tyr(423) of CadB, and Cys(62), Trp(201), Glu(207), Trp(292), and Tyr(425) of PotE are strongly involved in the antiport activities. In addition, Trp(43), Tyr(57), Tyr(107), Tyr(366), and Tyr(368) of CadB are involved preferentially in cadaverine uptake at neutral pH, while only Tyr(90) of PotE is involved preferentially in putrescine uptake. The results indicated that the central cavity of CadB consists of TMs 2, 3, 6, 7, 8, and 10, and that of PotE consists of TMs 2, 3, 6, and 8. Several residues are necessary for recognition of cadaverine in the periplasm because the level of cadaverine is much lower than that of putrescine at neutral pH.^[6]

The roughly barrel-shaped AdiC subunit of approx. 45 Å diameter consists of 12 transmembrane helices, TMS1 and TMS6 being interrupted by short non-helical stretches in the middle of their transmembrane spans.^[11] Biochemical analysis of homologues places the amino and carboxy termini on the intracellular side of the membrane. TM1–TM10 surround a large cavity exposed to the extracellular solution. These ten helices comprise two inverted structural repeats. TM1–TM5 of AdiC align well with TM6–TM10 turned 'upside down' around a pseudo-two-fold axis nearly parallel to the membrane plane. Thus, TMS1 pairs with TMS6, TMS2 with TMS7, etc. Helices TMS11 and TMS12, non-participants in this repeat, provide most of the 2,500 Å 2 homodimeric interface. AdiC mirrors the common fold observed unexpectedly in four phylogenetically unrelated families of Na⁺-coupled solute transporters: BCCT (2.A.15), NCS1 (2.A.39), SSS (2.A.21) and NSS (2.A.22).^[6]^[11]

Transport reactions

Transport reactions generally catalyzed by APC superfamily members include:^[6]

Solute:proton symport

Solute (out) + nH⁺ (out) → Solute (in) + nH⁺ (in).

Solute:solute antiport

Solute-1 (out) + Solute-2 (in) ⇌ Solute-1 (in) + Solute-2 (out).

These reactions may differ for some family members.

Related Research Articles

The Transporter Classification Database is an International Union of Biochemistry and Molecular Biology (IUBMB)-approved classification system for membrane transport proteins, including ion channels.

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na⁺ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

An amino acid transporter is a membrane transport protein that transports amino acids. They are mainly of the solute carrier family.

<span class="mw-page-title-main">Betaine transporter</span> Family of transport proteins

The Betaine/Carnitine/Choline Transporter (BCCT) family proteins are found in Gram-negative and Gram-positive bacteria and archaea. The BCCT family members a large group of secondary transporters, the APC superfamily. Their common functional feature is that they all transport molecules with a quaternary ammonium group [R-N (CH₃)₃]. The BCCT family proteins vary in length between 481 and 706 amino acyl residues and possess 12 putative transmembrane α-helical spanners (TMSs). The x-ray structures reveal two 5 TMS repeats, with the total TMSs being 10. These porters catalyze bidirectional uniport or are energized by pmf-driven or smf-driven proton or sodium ion symport, respectively, or substrate: substrate antiport. Some of these permeases exhibit osmosensory and osmoregulatory properties inherent to their polypeptide chains.

The Nucleobase:Cation Symporter-1 (NCS1) Family (TC# 2.A.39) consists of over 1000 currently sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, fungi and plants. These proteins function as transporters for nucleobases including purines and pyrimidines. Members of this family possess twelve transmembrane α-helical spanners (TMSs). At least some of them have been shown to function in uptake by substrate:H⁺ symport mechanism.

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na⁺ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na⁺ symport.

The Nucleobase cation symporter-2 (NCS2) family, also called the Nucleobase ascorbate transporter (NAT) family, consists of over 1000 sequenced proteins derived from gram-negative and gram-positive bacteria, archaea, fungi, plants and animals. The NCS2/NAT family is a member of the APC Superfamily of secondary carriers. Of the five known families of transporters that act on nucleobases, NCS2/NAT is the only one that is most widespread. Many functionally characterized members are specific for nucleobases including both purines and pyrimidines, but others are purine-specific. However, two closely related rat/human members of the family, SVCT1 and SVCT2, localized to different tissues of the body, co-transport L-ascorbate (vitamin C) and Na⁺ with a high degree of specificity and high affinity for the vitamin. Clustering of NCS2/NAT family members on the phylogenetic tree is complex, with bacterial proteins and eukaryotic proteins each falling into at least three distinct clusters. The plant and animal proteins cluster loosely together, but the fungal proteins branch from one of the three bacterial clusters forming a tighter grouping. E. coli possesses four distantly related paralogous members of the NCS2 family.

It has been shown that integral membrane proteins that mediate the uptake of a wide variety of molecules with the concomitant uptake of sodium ions can be grouped, on the basis of sequence and functional similarities into a number of distinct families. One of these families is known as the sodium:dicarboxylate symporter family (SDF).

The transporter-opsin-G protein-coupled receptor (TOG) superfamily is a protein superfamily of integral membrane proteins, usually of 7 or 8 transmembrane alpha-helical segments (TMSs). It includes (1) ion-translocating microbial rhodopsins and (2) G protein-coupled receptors (GPCRs), (3) Sweet sugar transporters, (4) nicotinamide ribonucleoside uptake permeases (PnuC; TC# 4.B.1), (5) 4-toluene sulfonate uptake permeases (TSUP); TC# 2.A.102), (6) Ni²⁺–Co²⁺ transporters (NiCoT); TC# 2.A.52), (7) organic solute transporters (OST); TC# 2.A.82), (8) phosphate:Na⁺ symporters (PNaS); TC# 2.A.58) and (9) lysosomal cystine transporters (LCT); TC# 2.A.43).

The Amino Acid-Polyamine-Organocation (APC) Family of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters. They occur in bacteria, archaea, fungi, unicellular eukaryotic protists, slime molds, plants and animals. They vary in length, being as small as 350 residues and as large as 850 residues. The smaller proteins are generally of prokaryotic origin while the larger ones are of eukaryotic origin. Most of them possess twelve transmembrane α-helical spanners but have a re-entrant loop involving TMSs 2 and 3. The APC Superfamily was established to encompass a wider range of homologues.

Members of the Alanine or Glycine:Cation Symporter (AGCS) Family (TC# 2.A.25) transport alanine and/or glycine in symport with Na⁺ and or H⁺.

The branched chain amino acid:cation symporter (LIVCS) family (TC# 2.A.26) is a member of the APC superfamily. Characterized members of this family transport all three of the branched chain aliphatic amino acids (leucine (L), isoleucine (I) and valine (V)). These proteins are found in Gram-negative and Gram-positive bacteria and function by a Na⁺ or H⁺ symport mechanism. They possess about 440 amino acyl residues and display 12 putative transmembrane helical spanners. As of early 2016, no crystal structures for members of the LIVCS family are available on RCSB.

The Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family is a member of the large Amino Acid-Polyamine-OrganoCation (APC) Superfamily of secondary carrier proteins. Members of the HAAAP family all function in amino acid uptake. Homologues are present in many Gram-negative and Gram-positive bacteria, with at least one member classified from archaea .

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

The sulfate permease (SulP) family is a member of the large APC superfamily of secondary carriers. The SulP family is a large and ubiquitous family of proteins derived from archaea, bacteria, fungi, plants and animals. Many organisms including Bacillus subtilis, Synechocystis sp, Saccharomyces cerevisiae, Arabidopsis thaliana and Caenorhabditis elegans possess multiple SulP family paralogues. Many of these proteins are functionally characterized, and most are inorganic anion uptake transporters or anion:anion exchange transporters. Some transport their substrate(s) with high affinities, while others transport it or them with relatively low affinities. Others may catalyze SO²⁻
₄:HCO⁻
₃ exchange, or more generally, anion:anion antiport. For example, the mouse homologue, SLC26A6, can transport sulfate, formate, oxalate, chloride and bicarbonate, exchanging any one of these anions for another. A cyanobacterial homologue can transport nitrate. Some members can function as channels. SLC26A3 and SLC26A6 can function as carriers or channels, depending on the transported anion. In these porters, mutating a glutamate, also involved in transport in the CIC family, created a channel out of the carrier. It also changed the stoichiometry from 2Cl⁻/HCO⁻
₃ to 1Cl⁻/HCO⁻
₃.

The potassium (K⁺) uptake permease (KUP) family (TC# 2.A.72) is a member of the APC superfamily of secondary carriers. Proteins of the KUP/HAK/KT family include the KUP (TrkD) protein of E. coli and homologues in both Gram-positive and Gram-negative bacteria. High affinity (20 μM) K⁺ uptake systems (Hak1, TC# 2.A.72.2.1) of the yeast Debaryomyces occidentalis as well as the fungus, Neurospora crassa, and several homologues in plants have been characterized. Arabidopsis thaliana and other plants possess multiple KUP family paralogues. While many plant proteins cluster tightly together, the Hak1 proteins from yeast as well as the two Gram-positive and Gram-negative bacterial proteins are distantly related on the phylogenetic tree for the KUP family. All currently classified members of the KUP family can be found in the Transporter Classification Database.

Divalent anion:Na⁺ symporters were found in bacteria, archaea, plant chloroplasts and animals.

The ion transporter (IT) superfamily is a superfamily of secondary carriers that transport charged substrates.

The arsenical resistance-3 (ACR3) family is a member of the BART superfamily. Based on operon analyses, ARC3 homologues may function either as secondary carriers or as primary active transporters, similarly to the ArsB and ArsAB families. In the latter case ATP hydrolysis again energizes transport. ARC3 homologues transport the same anions as ArsA/AB homologues, though ArsB homologues are members of the IT Superfamily and homologues of the ARC3 family are within the BART Superfamily suggesting they may not be evolutionarily related.

The cation:proton antiporter (CPA) superfamily is a superfamily of transport proteins named after one of its constituent members, the monovalent cation:proton antiporter-2 (CPA2).

References

↑ Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH (October 2014). "Expansion of the APC superfamily of secondary carriers". Proteins. 82 (10): 2797–811. doi:10.1002/prot.24643. PMC 4177346 . PMID 25043943.
1 2 Höglund, Pär J.; Nordström, Karl J. V.; Schiöth, Helgi B.; Fredriksson, Robert (April 2011). "The solute carrier families have a remarkably long evolutionary history with the majority of the human families present before divergence of Bilaterian species". Molecular Biology and Evolution. 28 (4): 1531–1541. doi:10.1093/molbev/msq350. ISSN 1537-1719. PMC 3058773 . PMID 21186191.
1 2 3 4 Perland, Emelie; Fredriksson, Robert (March 2017). "Classification Systems of Secondary Active Transporters". Trends in Pharmacological Sciences. 38 (3): 305–315. doi:10.1016/j.tips.2016.11.008. ISSN 1873-3735. PMID 27939446.
↑ Wipf D, Ludewig U, Tegeder M, Rentsch D, Koch W, Frommer WB (March 2002). "Conservation of amino acid transporters in fungi, plants and animals". Trends in Biochemical Sciences. 27 (3): 139–47. doi:10.1016/s0968-0004(01)02054-0. PMID 11893511.
↑ Fischer, WN; André, B; Rentsch, D; Krolkiewics, S; Tegeder, M; Breitkreuz, K; Frommer, WB (1998). "Amino acid transport in plants". Trends Plant Sci. 3 (188–195): 188–195. doi:10.1016/S1360-1385(98)01231-X.
1 2 3 4 5 6 Saier, MH Jr. "2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily". Transporter Classification Database. Saier Lab Bioinformatics Group.
↑ Hediger, Matthias A.; Romero, Michael F.; Peng, Ji-Bin; Rolfs, Andreas; Takanaga, Hitomi; Bruford, Elspeth A. (February 2004). "The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction". Pflügers Archiv: European Journal of Physiology. 447 (5): 465–468. doi:10.1007/s00424-003-1192-y. ISSN 0031-6768. PMID 14624363. S2CID 1866661.
1 2 Soksawatmaekhin W, Uemura T, Fukiwake N, Kashiwagi K, Igarashi K (September 2006). "Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB". The Journal of Biological Chemistry. 281 (39): 29213–20. doi: 10.1074/jbc.m600754200 . PMID 16877381.
↑ Forrest LR, Rudnick G (December 2009). "The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters". Physiology. 24 (6): 377–86. doi:10.1152/physiol.00030.2009. PMC 3012352 . PMID 19996368.
↑ Rudnick G (September 2011). "Cytoplasmic permeation pathway of neurotransmitter transporters". Biochemistry. 50 (35): 7462–75. doi:10.1021/bi200926b. PMC 3164596 . PMID 21774491.
1 2 Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C (August 2009). "Structure of a prokaryotic virtual proton pump at 3.2 A resolution". Nature. 460 (7258): 1040–3. doi:10.1038/nature08201. PMC 2745212 . PMID 19578361.