APC Family

Last updated
Identifiers
SymbolAPC
Pfam PF00324
InterPro IPR004841
TCDB 2.A.3
OPM superfamily 64
OPM protein 3gia

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

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

Mitochondrial carrier

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.

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.

Betaine transporter Family of transport proteins

Proteins of the Betaine/Carnitine/Choline Transporter (BCCT) family are found in Gram-negative and Gram-positive bacteria and archaea. The BCCT family is a member 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 number of TMSs being 10. These porters catalyze bidirectional uniport or are energized by pmf-driven or smf-driven proton or sodium ion symport, respectively, or else by 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.

Sodium-solute symporter 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.

Mercury transporter

The mercury transporter superfamily is a family of transmembrane bacterial transporters of mercury ions. The common origin of all Mer superfamily members has been established. The common elements between family members are included in TMSs 1-2. A representative list of the subfamilies and proteins that belong to those subfamilies is available in the Transporter Classification Database.

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 a large number of Gram-negative and Gram-positive bacteria, with at least one member classified from archaea .

The benzoate:H symporter (BenE) family is a member of the APC Superfamily. The BenE family contains only two functionally characterized and sequenced members, the benzoate permeases of Acinetobacter calcoaceticus and E. coli. These proteins are about 400 residues in length and probably span the membrane 12 times. Some members of the BenE family can have as little as 7 TMSs, or as many as 14 TMSs. BenE family members exhibit about 30% identity to each other and limited sequence similarity to members of the Aromatic Acid:H Symporter (AAHS) family of the Major Facilitator Superfamily (MFS). The degree of similarity with the latter proteins is insufficient to establish homology. As of early 2016, no crystal structural data is available for members of the BenE family.

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 is a family of transporter proteins belonging to the ion transporter (IT) superfamily. The AbgT family consists of the AbgT protein of E. coli and the MtrF drug exporter 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 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 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. Current Topics in Membranes. Vol. 70. pp. 1–28. doi:10.1016/B978-0-12-394316-3.00001-6. ISBN   9780123943163. PMID   23177982.
  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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