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Identifiers
SymbolAPC
PfamPF0034
InterProIPR004841
TCDB2.A.3
OPM superfamily67
OPM protein3gia
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure 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] 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.[4][5] The APC family (TC# 2.A.3) used serve as a sort of superfamily for solute:cation and solute:solute porters and includes several subfamilies, hence the reoccurring use of "superfamily" on the APC family page. The APC Superfamily was later established to encompass a wider range of homologues after extensive bioinformatic and phylogenetic analysis. TCDB embodies a static system for numbering and classification, therefore the APC family classification could not be altered to accommodate newly discovered relatives.

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 [6] and are truncated at their C-termini, relative to the transporters, having 10 TMSs.[7]

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.[8]

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.[9] They are members of the rBAT family of mammalian proteins (TC #8.A.9).

Two APC family members, LAT1 and LAT2 (TC #2.A.3.8.7), transport a neurotoxicant, the methylmercury-L-cysteine complex, by molecular mimicry.[10]

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:[5]

  • 2.A.3.1: The Amino Acid Transporter (AAT) Family
  • 2.A.3.2: The Basic Amino Acid/Polyamine Antiporter (APA) Family
  • 2.A.3.3: The Cationic Amino Acid Transporter (CAT) Family
  • 2.A.3.4: The Amino Acid/Choline Transporter (ACT) Family
  • 2.A.3.5: The Ethanolamine Transporter (EAT) Family
  • 2.A.3.6: The Archaeal/Bacterial Transporter (ABT) Family
  • 2.A.3.7: The Glutamate:GABA Antiporter (GGA) Family
  • 2.A.3.8: The L-type Amino Acid Transporter (LAT) Family (Many LAT family members function as heterooligomers with rBAT and/or 4F2hc (TC #8.A.9))
  • 2.A.3.9: The Spore Germination Protein (SGP) Family
  • 2.A.3.10: The Yeast Amino Acid Transporter (YAT) Family
  • 2.A.3.11: The Aspartate/Glutamate Transporter (AGT) Family
  • 2.A.3.12: The Polyamine:H+ Symporter (PHS) Family
  • 2.A.3.13: The Amino Acid Efflux (AAE) Family
  • 2.A.3.14: The Unknown APC-1 (U-APC1) Family
  • 2.A.3.15: The Unknown APC-2 (U-APC2) Family

Structure and Function

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.[11] A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII.[11] Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "rocking bundle" mechanism.[5][12][13]

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.[5]

Transport Reactions

Transport reactions generally catalyzed by APC Superfamily members include:[5]

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

References

  1. ^ a b Saier, MH Jr. (August 2000). "Families of transmembrane transporters selective for amino acids and their derivatives". Microbiology. 146 (8): 1775–95. doi:10.1099/00221287-146-8-1775. PMID 10931885.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Wong, FH; Chen, JS; Reddy, V; Day, JL; Shlykov, MA; Wakabayashi, ST; Saier, MH Jr. (2012). "The amino acid-polyamine-organocation superfamily". J Mol Microbiol Biotechnol. 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. 70: 1–28. doi:10.1016/B978-0-12-394316-3.00001-6. PMID 23177982.
  4. ^ Gasol, E; Jiménez-Vidal, M; Chillarón, J; Zorzano, A; Palacín, M (July 23, 2014). "Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility". Journal of Biological Chemistry. 279 (30): 31228–36. doi:10.1074/jbc.M402428200. PMID 15151999.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b c d e Saier, MH Jr. "2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
  6. ^ 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.
  7. ^ 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 (8): 1797–814. doi:10.1099/00221287-146-8-1797. PMID 10931886.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Lorca, G; Winnen, B; Saier, MH Jr. (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.
  9. ^ Sato, H; Shiiya, A; Kimata, M; Maebara, K; Tamba, M; Sakakura, Y; Makino, N; Sugiyama, F; Yagami, K; Moriguchi, T; Takahashi, S; Bannai, S (Nov 11, 2005). "Redox imbalance in cystine/glutamate transporter-deficient mice". Journal of Biological Chemistry. 280 (45): 37423–9. doi:10.1074/jbc.m506439200. PMID 16144837.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Simmons-Willis, TA; Koh, AS; Clarkson, TW; Ballatori, N (October 1, 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". Biochemical Journal. 367 (1): 239–46. doi:10.1042/bj20020841. PMC 1222880. PMID 12117417.
  11. ^ a b Soksawatmaekhin, W; Uemura, T; Fukiwake, N; Kashiwagi, K; Igarashi, K (Sep 29, 2006). "Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB". Journal of Biological Chemistry. 281 (39): 29213–20. doi:10.1074/jbc.m600754200. PMID 16877381.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Forrest, L; Rudnick, G (December 8, 2009). "The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters". American Physiological Society. 24 (6): 377–386. doi:10.1152/physiol.00030.2009.
  13. ^ Rudnick, G (2011). "Cytoplasmic permeation pathway of neurotransmitter transporters". Biochemistry. 50 (35): 7462–7475. doi:10.1021/bi200926b.
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