2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily
The APC superfamily of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters (Saier, 2000). They occur in bacteria, archaea, yeast, fungi, unicellular eukaryotic protists, slime molds, plants and animals (Saier, 2000). 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 (Gasol et al., 2004). Members of one family within the APC superfamily (SGP; TC# 2.A.3.9) are amino acid receptors rather than transporters (Cabrera-Martinez et al., 2003), and are truncated at their C-termini, relative to the transporters, having 10 TMSs (Jack et al., 2000). The eukaryotic members of another family (CAT; TC# 2.A.3.3) and the members of a prokaryotic family (AGT; TC #2.A.3.11) have 14 TMSs (Lorca et al., 2003). The larger eukaryotic and archaeal proteins possess N- and C-terminal hydrophilic extensions. Some animal proteins, for example, those in the LAT family (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 (Sato et al., 2005). 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 (Simmons-Willis et al., 2002). Hip1 of S. cerevisiae (TC #2.A.3.1.5) has been implicated in heavy metal transport. Distant constituents of the APC superfamily are the AAAP family (TC# 2.A.18), the ArAAP family (TC# 2.A.42) and the STP family (TC# 2.A.43). Some of these proteins exhibit 11 TMSs. Eukaryotic members of this superfamily have been reviewed by Wipf et al. (2002) and Fischer et al. (1998).
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 (Soksawatmaekhin et al., 2006). A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII (Soksawatmaekhin et al., 2006).
Shaffer et al. (2009) have presented the crystal structure of apo-ApcT, a proton-coupled broad-specificity amino acid transporter, at 2.35 Å resolution. The structure contains 12 transmembrane helices, with the first 10 consisting of an inverted structural repeat of 5 transmembrane helices like LeuT (TC #2.A.22.4.2). The ApcT structure reveals an inward-facing, apo state and an amine moiety of Lys158 located in a position equivalent to the Na2 ion of LeuT. They proposeed that Lys158 is central to proton-coupled transport and that the amine group serves the same functional role as the Na2 ion in LeuT, thus demonstrating common principles among proton- and sodium-coupled transporters.
The roughly barrel-shaped AdiC subunit of 
45 Å diameter consists of 12 transmembrane helices, TMS1 and TMS6 being interrupted by short
non-helical stretches in the middle of their transmembrane spans (Fang et al., 2009).
Biochemical analysis of homologues places the amino and carboxy termini
on the intracellular side of the membrane.
TM1–TM10 surround a large cavity exposed to the extracellular solution.
These ten helices comprise two inverted structural
repeats.
TM1–TM5 of AdiC align well with TM6–TM10 turned 'upside down' around a
pseudo-two-fold axis nearly parallel to the membrane plane. Thus, TMS1 pairs with TMS6, TMS2 with TMS7, and etc.. Helices TMS11 and TMS12,
non-participants in this repeat, provide most of the 2,500 Å2 homodimeric interface. AdiC mirrors the common fold observed
unexpectedly in four phylogenetically unrelated families of Na+-coupled solute transporters: BCCT (2.A.15), NCS1 (2.A.39), SSS (2.A.21) and NSS (2.A.22) (Fang et al., 2009).
Transport reactions catalyzed by APC family members include:
Solute:proton symport - S (out) + nH+ (out) → S (in) + nH+ (in).
Solute:solute antiport - S1 (out) + S2 (in) 
S1 (in) + S2 (out).
