APC Family

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.

Identifiers
SymbolAPC
PfamPF00324
InterProIPR004841
TCDB2.A.3
OPM superfamily64
OPM protein3gia
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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]

  • 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

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

References
  1. 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. 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. 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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