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APC superfamily

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The Amino Acid-Polyamine-Organocation (APC) Superfamily (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, yeast, 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]


Members of APC Superfamily

Members of one family within the APC superfamily (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 family (CAT; TC# 2.A.3.3) and the members of a prokaryotic family (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 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 [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. Distant constituents of the APC superfamily are the AAAP family (TC# 2.A.18), the HAAAP family (TC# 2.A.42) and the LCT 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) [11] and Fischer et al. (1998) [12]. [5]


Families

Currently recognized families within the APC Superfamily (with TC numbers in blue) include: [5]

  • 2.A.3 - The Amino Acid-Polyamine-Organocation (APC) Family
  • 2.A.15 - The Betaine/Carnitine/Choline Transporter (BCCT) Family
  • 2.A.18 - The Amino Acid/Auxin Permease (AAAP) Family
  • 2.A.21 - The Solute:Sodium Symporter (SSS) Family
  • 2.A.22 - The Neurotransmitter:Sodium Symporter (NSS) Family
  • 2.A.25 - The Alanine or Glycine:Cation Symporter (AGCS) Family
  • 2.A.26 - The Branched Chain Amino Acid:Cation Symporter (LIVCS) Family
  • 2.A.30 - The Cation-Chloride Cotransporter (CCC) Family
  • 2.A.31 - The Anion Exchanger (AE) Family
  • 2.A.39 - The Nucleobase:Cation Symporter-1 (NCS1) Family
  • 2.A.40 - The Nucleobase/Ascorbate Transporter (NAT) or Nucleobase:Cation Symporter-2 (NCS2) Family
  • 2.A.42 - The Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family
  • 2.A.46 - The Benzoate:H+ Symporter (BenE) Family
  • 2.A.53 - The Sulfate Permease (SulP) Family
  • 2.A.55 - The Metal Ion (Mn2+-iron) Transporter (Nramp) Family
  • 2.A.72 - The K+ Uptake Permease (KUP) Family
  • 2.A.114 - The Putative Peptide Transporter Carbon Starvation CstA (CstA) Family
  • 2.A.120 - The Putative Amino Acid Permease (PAAP) 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 [13]. A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII [13]. Based on 3-d structures of APC superfamily members, Rudnick (2011) [14] [15] has proposed the pathway for transport and suggested a rocking bundle mechanism. [5]


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 [16]. 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 proposed 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. [5]


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. 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]


The roughly barrel-shaped AdiC subunit of approx. 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 [17]. 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 Å 2 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) [17]. [5]


Transport Reactions

Transport reactions catalyzed by APC family 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).


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. PMID 10931885.
  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. PMID 15151999.
  5. ^ a b c d e f g h Saier, MH Jr. "2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily". Transporter Classification Database. Saier Lab Bioinformatics Group.
  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. 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. PMID 10931886.
  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. 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. PMID 16144837.
  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. PMID 12117417.
  11. ^ Wipf, D; Ludewig, U; Tegeder, M; Rentsch, D; Koch, W; Frommer, WB (March 2000). "Conservation of amino acid transporters in fungi, plants and animals". Trends in Biochemical Sciences. 27 (3): 139–47. PMID 11893511.
  12. ^ Fischer, WN; André, B; Rentsch, D; Krolkiewics, S; Tegeder, M; Breitkreuz, K; Frommer, WB (1998). "Amino acid transport in plants". Trends Plant Sci. 3 (188–195).
  13. ^ 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. PMID 16877381.
  14. ^ 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.
  15. ^ Rudnick, G (2011). "Cytoplasmic permeation pathway of neurotransmitter transporters". Biochemistry. 50 (35): 7462–7475. doi:10.1021/bi200926b.
  16. ^ Shaffer, PL; Goehring, A; Shankaranarayanan, A; Gouaux, E (August 21, 2009). "Structure and mechanism of a Na+-independent amino acid transporter". Science. 325 (5943): 1010–4. doi:10.1126/science.1176088. PMID 19608859.
  17. ^ a b Fang, Y; Jayaram, H; Shane, T; Kolmakova-Partensky, L; Wu, F; Williams, C; Xiong, Y; Miller, C (August 20, 2009). "Structure of a prokaryotic virtual proton pump at 3.2 A resolution". Nature. 460 (7258): 1040–3. doi:10.1038/nature08201.
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