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APC Superfamily

The amino acid/polyamine/organocation (APC) superfamily is among the largest transport superfamilies identified. It is found in all forms of life. However, not much is known about the structures of members of this family, because only one has been successfully analyzed by x-ray chromatography. This one structure lends much insight into the qualities of the superfamily as a whole when compared with existing hydropathy plots and other studies.

Superfamilies have been identified using phylogenetic analysis. Thus, only proteins with similar genetic qualities and evolutionary roots are considered members of the same superfamily. Because of this, proteins with similar topographies are not necessarily in the same superfamily. For instance, the core structure of AdiC, a member of the APC superfamily discussed below, is very similar to that of LeuT (a member of the neurotransmitter sodium symporter (NSS) family), BetP (a member of the betaine/chlorine/carnitine transporter (BCCT) family), vSGLT (of the solute sodium symporter (SSS) family) and Mhb1 (of the nucleobase-cation-symport-1 (NCS1) family).

According to hydropathy plots[1], all members of the APC superfamily exhibit a uniform topology formed by a single polypeptide chain that crosses the plasma membrane 12 times, unless otherwise noted. Each protein's N- and C-termini are located in the cytosol. The loops in the cytosol tend to be smaller than the loops located in the extracellular space.

10 established protein families

AAT: Amino Acid Transporter

Unique to bacteria, this is the largest family within the APC superfamily. Members of this family have short hydrophilic extensions at both termini.

APA: Basic Amino Acid/Polyamine Transporter

The APA family is also unique to bacteria.

CAT: Cationic Amino Acid Transporter

Members of the CAT family are ubiquitous, containing 14 TMs in eukaryotes and 12 TMs in prokaryotes. These proteins have short, hydrophilic, N-terminal extensions.

ACT: Amino Acid/Choline Transporter

Members of the CAT family can be found in yeast, plants, and fungi. These proteins have short hydrophilic extensions at the C and N termini.

EAT: Ethanolamine Transporter

Members of the EAT family are found in bacteria. They have no noticeable extensions beyond the 12 TMs.

ABT: Archaeal/Bacterial Transporter

As the name suggests, members of the ABT family are found in archaea and bacteria. One member (Cat1 Afu) of this family exhibits a long, C-terminal extension that may function in interactions with other proteins.

GGA: Glutamate:GABA Antiporter

Members of the GGA family are found only in bacteria. There proteins have short, hydrophilic, N-terminal extensions.

LAT: L-type Amino Acid Transporter

Members of the LAT family have been identified in animals and yeast.

SPG: Spore Germination Protein

Members of this family are found in prokaryotes and exhibit only 10 transmembrane segments. The 2 segments closest to the C-terminus in other members of this super family appear to have been cleaved when this family was evolving. None of the proteins in this family have been identified as transporters, leading to the possibility that transmembrane segments 11 and 12 are vital for transport function.

YAT: Yeast Amino Acid Transporter

Members of the YAT family have been identified in both yeast and fungi. Some members of this family exhibit long, N-terminal, hydrophilic extensions beyond the 12 TMs.


AdiC - an example from the APA family

AdiC has been determined to be a member of the APC superfamily through phylogenetic analysis.

AdiC is a representative member of the APC superfamily; it contains 12 TMs with each termini located in the cytosol. AdiC functions as an arginine/agmatine antiporter in E. coli and other bacteria when the cell is exposed to acidic environments. Agmatine is the product of arginine decarboxylation. An associated protein, AdiA, is thought to decarboxylate arginine molecules for transport. By exchanging intracellular agmatine (Agm(2+)) for extracellular arginine (Arg(+)), AdiC removes virtual protons from the interior of the cell, enabling the bacteria to survive in acidic conditions by preventing acidification of the cytosol.

Outward-facing AdiC homodimer

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Though the structure is shown as a homodimer, each subunit is an independently functioning transporter. [2] where the N-terminus is gradually shaded into the C-terminus according to the scale below.
N               C

The transmembrane helices surround the pore in antiparallel fashion, with TM1 paired with TM6, TM2 with TM7, and so on. TMs 11 and 12 do not participate in this pairing scheme; instead, they form most of the homodimeric interface. TMs 1 and 6 contain a short, non-helical segment midway across the membrane, thought to be important for substrate interactions [3].

AdiC in complex with Arginine and B-Nonylglucoside [3L1L]

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Arg binding induces a structural rearrangement in TM6 and minor changes in TM2 and TM10, resulting in an occluded formation [4].

Trp-293 has been demonstrated to be vital for substrate recognition [5]. Trp-293 is buried in the substrate-binding site, Notice the aromatic interactions with the substrate. Tyr-93 is another residue proposed to be vital for substrate specificty and/or binding, Trp-293 and Tyr-93 come from TM8 and TM3, respectively. Glu-208 may also play a part in regulating the upload and release of substrate

LAT1 and SteT - examples from the LAT family

References

  1. ↑ Jack DL, Paulsen IT, Saier MH. The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations. Microbiology. 2000 Aug;146 ( Pt 8):1797-814. PMID:10931886
  2. ↑ Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C. Structure of a prokaryotic virtual proton pump at 3.2 A resolution. Nature. 2009 Aug 20;460(7258):1040-3. Epub 2009 Jul 5. PMID:19578361 doi:10.1038/nature08201
  3. ↑ Gao X, Lu F, Zhou L, Dang S, Sun L, Li X, Wang J, Shi Y. Structure and mechanism of an amino acid antiporter. Science. 2009 Jun 19;324(5934):1565-8. Epub 2009 May 28. PMID:19478139
  4. ↑ Gao X, Zhou L, Jiao X, Lu F, Yan C, Zeng X, Wang J, Shi Y. Mechanism of substrate recognition and transport by an amino acid antiporter. Nature. 2010 Feb 11;463(7282):828-32. Epub 2010 Jan 20. PMID:20090677 doi:10.1038/nature08741
  5. ↑ Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C. Structure of a prokaryotic virtual proton pump at 3.2 A resolution. Nature. 2009 Aug 20;460(7258):1040-3. Epub 2009 Jul 5. PMID:19578361 doi:10.1038/nature08201

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Jennifer VanAusdall

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