APC Family

Last updated
Identifiers
SymbolAPC
Pfam PF00324
InterPro IPR004841
TCDB 2.A.3
OPM superfamily 64
OPM protein 3gia
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The Amino Acid-Polyamine-Organocation (APC) Family (TC# 2.A.3) of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters. [1] [2] [3] [4] They occur in bacteria, archaea, fungi, unicellular eukaryotic protists, slime molds, plants and animals. [1] 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. [5] [6] The APC Superfamily was established to encompass a wider range of homologues.

Contents

Members of APC Family

Members of one subfamily within the APC family (SGP; TC# 2.A.3.9) are amino acid receptors rather than transporters [7] and are truncated at their C-termini, relative to the transporters, having 10 TMSs. [8]

The eukaryotic members of another subfamily (CAT; TC# 2.A.3.3) and the members of a prokaryotic subfamily (AGT; TC #2.A.3.11) have 14 TMSs. [9]

The larger eukaryotic and archaeal proteins possess N- and C-terminal hydrophilic extensions. Some animal proteins, for example, those in the LAT subfamily (TC# 2.A.3.8) including ASUR4 (gbY12716) and SPRM1 (gbL25068) associate with a type 1 transmembrane glycoprotein that is essential for insertion or activity of the permease and forms a disulfide bridge with it. These glycoproteins include the CD98 heavy chain protein of Mus musculus (gbU25708) and the orthologous 4F2 cell surface antigen heavy chain of Homo sapiens (spP08195). The latter protein is required for the activity of the cystine/glutamate antiporter (2.A.3.8.5), which maintains cellular redox balance and cysteine/glutathione levels. [10] They are members of the rBAT family of mammalian proteins (TC #8.A.9).

Most S. cerevisiae amino acid permeases are members of the APC family. The majority of these permeases belong to the YAT sub-family (2.A.3.10) and they have a broad range of overlapping specificities. Two additional permeases belong to the LAT sub-family (2.A.3.8.4 and 2.A.3.8.16) and support methionine and cysteine intake. The final one identified is an ACT sub-family (2.A.3.4.3) member, a GABA permease, present in both cell and vacuolar membranes; all others are found only in the cell membrane. [11]

Two APC family members, LAT1 and LAT2 (TC #2.A.3.8.7), transport a neurotoxicant, the methylmercury-L-cysteine complex, by molecular mimicry. [12]

Hip1 of S. cerevisiae (TC #2.A.3.1.5) has been implicated in heavy metal transport.

Subfamilies

Subfamilies of the APC family, and the proteins in these families, can be found in the Transporter Classification Database: [6]

Structure and function

Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "rocking bundle" mechanism. [6] [13] [14]

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).

See also

Related Research Articles

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

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.

<span class="mw-page-title-main">Large neutral amino acids transporter small subunit 2</span> Protein-coding gene in the species Homo sapiens

Large neutral amino acids transporter small subunit 2 is a protein that in humans is encoded by the SLC7A8 gene.

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">Sodium-solute symporter</span> Group of transport proteins

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.

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) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

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 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 putative amino acid permease (PAAP) family belongs to the APC superfamily. The PAAP family consists of many proteins, all of a uniform topology with a 5 + 5 TMS repeat in a 2 + 3 + 2 + 3 arrangement. These proteins show similarity to members of the LIVCS family in the APC Superfamily. A representative list of recognized members of the PAAP family is available 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 p-aminobenzoyl-glutamate transporter(AbgT) family (TC# 2.A.68) is a family of transporter proteins belonging to the ion transporter (IT) superfamily. The AbgT family consists of the AbgT (YdaH; TC# 2.A.68.1.1) protein of E. coli and the MtrF drug exporter (TC# 2.A.68.1.2) of Neisseria gonorrhoeae. The former protein is apparently cryptic in wild-type cells, but when expressed on a high copy number plasmid, or when expressed at higher levels due to mutation, it appeared to allow uptake (Km = 123 nM; see Michaelis–Menten kinetics) and subsequent utilization of p-aminobenzoyl-glutamate as a source of p-aminobenzoate for p-aminobenzoate auxotrophs. p-Aminobenzoate is a constituent of and a precursor for the biosynthesis of folic acid. MtrF was annotated as a putative drug efflux pump.

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

The lactate permease (LctP) family is a family of transport proteins belonging to the ion transporter (IT) superfamily.

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 Basic Amino Acid Antiporter (ArcD) family is a constituent of the IT superfamily. This family consists of proteins from Gram-negative and Gram-positive bacteria. The proteins are of about 480 amino acyl residues (aas) in length and have 10-12 putative transmembrane segments (TMSs). Functionally characterized homologues are in the DcuC and ArsB families. Some members of the family probably catalyze arginine/ornithine or citrulline/ornithine antiport.

References

  1. 1 2 Saier MH (August 2000). "Families of transmembrane transporters selective for amino acids and their derivatives". Microbiology. 146 ( Pt 8) (8): 1775–95. doi: 10.1099/00221287-146-8-1775 . PMID   10931885.
  2. ↑ Wong FH, Chen JS, Reddy V, Day JL, Shlykov MA, Wakabayashi ST, Saier MH (2012). "The amino acid-polyamine-organocation superfamily". Journal of Molecular Microbiology and Biotechnology. 22 (2): 105–13. doi: 10.1159/000338542 . PMID   22627175.
  3. ↑ Schweikhard ES, Ziegler CM (2012). Amino acid secondary transporters: toward a common transport mechanism. Vol. 70. pp. 1–28. doi:10.1016/B978-0-12-394316-3.00001-6. ISBN   9780123943163. PMID   23177982.{{cite book}}: |journal= ignored (help)
  4. ↑ Perland E, Fredriksson R (March 2017). "Classification Systems of Secondary Active Transporters". Trends in Pharmacological Sciences. 38 (3): 305–315. doi:10.1016/j.tips.2016.11.008. PMID   27939446.
  5. ↑ Gasol E, Jiménez-Vidal M, Chillarón J, Zorzano A, Palacín M (July 2004). "Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility". The Journal of Biological Chemistry. 279 (30): 31228–36. doi: 10.1074/jbc.M402428200 . PMID   15151999.
  6. 1 2 3 4 Saier, MH Jr. "2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
  7. ↑ Cabrera-Martinez RM, Tovar-Rojo F, Vepachedu VR, Setlow P (April 2003). "Effects of overexpression of nutrient receptors on germination of spores of Bacillus subtilis". Journal of Bacteriology. 185 (8): 2457–64. doi:10.1128/jb.185.8.2457-2464.2003. PMC   152624 . PMID   12670969.
  8. ↑ Jack DL, Paulsen IT, Saier MH (August 2000). "The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations". Microbiology. 146 ( Pt 8) (8): 1797–814. doi: 10.1099/00221287-146-8-1797 . PMID   10931886.
  9. ↑ Lorca G, Winnen B, Saier MH (May 2003). "Identification of the L-aspartate transporter in Bacillus subtilis". Journal of Bacteriology. 185 (10): 3218–22. doi:10.1128/jb.185.10.3218-3222.2003. PMC   154055 . PMID   12730183.
  10. ↑ Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y, Makino N, Sugiyama F, Yagami K, Moriguchi T, Takahashi S, Bannai S (November 2005). "Redox imbalance in cystine/glutamate transporter-deficient mice". The Journal of Biological Chemistry. 280 (45): 37423–9. doi: 10.1074/jbc.m506439200 . PMID   16144837.
  11. ↑ Bianchi, Frans; van’t Klooster, Joury S.; Ruiz, Stephanie J.; Poolman, Bert (2019-10-16). "Regulation of Amino Acid Transport in Saccharomyces cerevisiae". Microbiology and Molecular Biology Reviews. 83 (4): e00024–19. doi:10.1128/MMBR.00024-19. ISSN   1092-2172. PMC   7405077 . PMID   31619504.
  12. ↑ Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N (October 2002). "Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2". The Biochemical Journal. 367 (Pt 1): 239–46. doi:10.1042/bj20020841. PMC   1222880 . PMID   12117417.
  13. ↑ 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.
  14. ↑ Rudnick G (September 2011). "Cytoplasmic permeation pathway of neurotransmitter transporters". Biochemistry. 50 (35): 7462–75. doi:10.1021/bi200926b. PMC   3164596 . PMID   21774491.
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