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] 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

• APC Superfamily
• Transporter Classification Database
• Membrane transport protein

References