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| {{Pfam_box | |||
| | Symbol = APC | |||
| | Name = | |||
| | image = | |||
| | width = | |||
| | caption = | |||
| | Pfam = | |||
| | Pfam_clan = CL0062 | |||
| | ECOD = 5051.1.1 | |||
| | InterPro = | |||
| | SMART = | |||
| | PROSITE = | |||
| | SCOP = | |||
| | TCDB = 2.A.3 | |||
| | OPM family = 64 | |||
| | OPM protein = | |||
| | PDB = | |||
| }} | |||
| The '''amino acid-polyamine-organocation''' ('''APC''') '''superfamily''' is the second largest ] of ] currently known,<ref name="Vastermark">{{cite journal | vauthors = Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH | title = Expansion of the APC superfamily of secondary carriers | journal = Proteins | volume = 82 | issue = 10 | pages = 2797–811 | date = October 2014 | pmid = 25043943 | pmc = 4177346 | doi = 10.1002/prot.24643 }}</ref> and it contains several ].<ref name="Höglund 1531–1541">{{Cite journal|last1=Höglund|first1=Pär J.|last2=Nordström|first2=Karl J. V.|last3=Schiöth|first3=Helgi B.|last4=Fredriksson|first4=Robert|date=April 2011|title=The solute carrier families have a remarkably long evolutionary history with the majority of the human families present before divergence of Bilaterian species|journal=Molecular Biology and Evolution|volume=28|issue=4|pages=1531–1541|doi=10.1093/molbev/msq350|issn=1537-1719|pmc=3058773|pmid=21186191}}</ref><ref name=":0">{{Cite journal|last1=Perland|first1=Emelie|last2=Fredriksson|first2=Robert|date=March 2017|title=Classification Systems of Secondary Active Transporters|journal=Trends in Pharmacological Sciences|volume=38|issue=3|pages=305–315|doi=10.1016/j.tips.2016.11.008|issn=1873-3735|pmid=27939446}}</ref> Originally, the APC superfamily consisted of subfamilies under the transporter classification number (TC # ). This superfamily has since been expanded to include eighteen different families. | |||
| The '''Amino Acid-Polyamine-Organocation (APC) Superfamily''' () of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters <ref name="Saier 2000">{{cite journal|last1=Saier|first1=MH Jr.|title=Families of transmembrane transporters selective for amino acids and their derivatives.|journal=Microbiology|date=August 2000|volume=146|issue=8|pages=1775-95|pmid=10931885}}</ref><ref name="Wong 2012">{{cite journal|last1=Wong|first1=FH|last2=Chen|first2=JS|last3=Reddy|first3=V|last4=Day|first4=JL|last5=Shlykov|first5=MA|last6=Wakabayashi|first6=ST|last7=Saier|first7=MH Jr.|title=The amino acid-polyamine-organocation superfamily|journal=J Mol Microbiol Biotechnol.|date=2012|volume=22|issue=2|pages=105-13|doi=10.1159/000338542|pmid=22627175}}</ref><ref name=Schweikhard>{{cite journal|last1=Schweikhard|first1=ES|last2=Ziegler|first2=CM|title=Amino acid secondary transporters: toward a common transport mechanism.|journal=Current Topics in Membranes|date=2012|volume=70|pages=1-28|doi=10.1016/B978-0-12-394316-3.00001-6|pmid=23177982}}</ref>. They occur in bacteria, archaea, yeast, fungi, unicellular eukaryotic protists, slime molds, plants and animals <ref name="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 <ref name=Gasol>{{cite journal|last1=Gasol|first1=E|last2=Jiménez-Vidal|first2=M|last3=Chillarón|first3=J|last4=Zorzano|first4=A|last5=Palacín|first5=M|title=Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility.|journal=Journal of Biological Chemistry|date=July 23, 2014|volume=279|issue=30|pages=31228-36|pmid=15151999}}</ref>. <ref name=TCDB /> | |||
| The most recent families added include the PAAP (Putative Amino Acid Permease), LIVCS (Branched Chain Amino Acid:Cation Symporter), NRAMP (Natural Resistance-Associated Macrophage Protein), CstA (Carbon starvation A protein), KUP (K<sup>+</sup> Uptake Permease), BenE (Benzoate:H<sup>+</sup> Virginia Symporter), and AE (Anion Exchanger). Bioinformatic and phylogenetic analysis is used to continually expand currently existing families and superfamilies. | |||
| Other constituents of the APC superfamily are the ] (), the HAAAP family () and the ] (). Some of these proteins exhibit 11 TMSs. Eukaryotic members of this superfamily have been reviewed by Wipf et al. (2002) <ref name="Wipf1">{{cite journal | vauthors = Wipf D, Ludewig U, Tegeder M, Rentsch D, Koch W, Frommer WB | title = Conservation of amino acid transporters in fungi, plants and animals | journal = Trends in Biochemical Sciences | volume = 27 | issue = 3 | pages = 139–47 | date = March 2002 | pmid = 11893511 | doi=10.1016/s0968-0004(01)02054-0}}</ref> and Fischer et al. (1998).<ref name="Fischer">{{cite journal|last1=Fischer|first1=WN|last2=André|first2=B|last3=Rentsch|first3=D|last4=Krolkiewics|first4=S|last5=Tegeder|first5=M|last6=Breitkreuz|first6=K|last7=Frommer|first7=WB|title=Amino acid transport in plants.|journal=Trends Plant Sci.|date=1998|volume=3|issue=188–195|pages=188–195|doi=10.1016/S1360-1385(98)01231-X|bibcode=1998TPS.....3..188F }}</ref><ref name="TCDB">{{cite web|last1=Saier|first1=MH Jr.|title=2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily|url=http://www.tcdb.org/search/result.php?tc=2.A.3|website=Transporter Classification Database|publisher=Saier Lab Bioinformatics Group}}</ref> | |||
| ==Families== | |||
| ==Members of APC Superfamily== | |||
| Currently recognized families within the APC Superfamily (with TC numbers in blue) include:<ref name=TCDB /> | |||
| Members of one family within the APC superfamily () are amino acid receptors rather than transporters <ref name=Cabrera>{{cite journal|last1=Cabrera-Martinez|first1=RM|last2=Tovar-Rojo|first2=F|last3=Vepachedu|first3=VR|last4=Setlow|first4=P|title=Effects of overexpression of nutrient receptors on germination of spores of Bacillus subtilis|journal=Journal of Bacteriology|date=April 2003|volume=185|issue=8|pages=2457-64|pmid=12670969}}</ref>, and are truncated at their C-termini, relative to the transporters, having 10 TMSs <ref name=Jack>{{cite journal|last1=Jack|first1=DL|last2=Paulsen|first2=IT|last3=Saier|first3=MH|title=The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations.|journal=Microbiology|date=August 2000|volume=146|issue=8|pages=1797-814|pmid=10931886}}</ref>. | |||
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| == APC proteins in humans == | |||
| There are several APC proteins expressed in humans, and they are ] proteins.<ref name=":0"/><ref>{{Cite journal|last1=Hediger|first1=Matthias A.|last2=Romero|first2=Michael F.|last3=Peng|first3=Ji-Bin|last4=Rolfs|first4=Andreas|last5=Takanaga|first5=Hitomi|last6=Bruford|first6=Elspeth A.|date=February 2004|title=The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction|journal=Pflügers Archiv: European Journal of Physiology|volume=447|issue=5|pages=465–468|doi=10.1007/s00424-003-1192-y|issn=0031-6768|pmid=14624363|s2cid=1866661}}</ref><ref name="Höglund 1531–1541"/> There are 11 SLC families including APC proteins: SLC4, 5, 6, 7, 11, 12, 23, 26, 32, 36, and 38.<ref name=":0" /> The ] ] is also clustered to the APC clan.<ref name=":0" /> | |||
| ==Structure and function== | |||
| The eukaryotic members of another family () and the members of a prokaryotic family () have 14 TMSs <ref name=Lorca>{{cite journal|last1=Lorca|first1=G|last2=Winnen|first2=B|last3=Saier|first3=MH Jr.|title=Identification of the L-aspartate transporter in Bacillus subtilis.|journal=Journal of Bacteriology|date=May 2003|volume=185|issue=10|pages=3218-22|pmid=12730183}}</ref>. | |||
| The topology of the well-characterized human Anion Exchanger 1 (AE1) conforms to a UraA-like topology of 14 TMSs (12 α-helical TMSs and 2 mixed coil/helical TMSs). All functionally characterized members of the APC superfamily use cation symport for substrate accumulation except for some members of the AE family which frequently use anion:anion exchange. All new entries contain the two 5 or 7 TMS repeat units characteristic of the APC superfamily, sometimes with extra TMSs at the ends likely the result of an addition prior to duplication. The CstA family contains the greatest variation in TMSs. New functionally characterized members transport amino acids, peptides, and inorganic anions or cations. Except for anions, these are typical substrates of established APC superfamily members. Active site TMSs are rich in glycyl residues in variable but conserved arrangements. | |||
| In CadB of ''E. coli'' (), 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.<ref name="Soksawatmaekhin 2006">{{cite journal | vauthors = Soksawatmaekhin W, Uemura T, Fukiwake N, Kashiwagi K, Igarashi K | title = Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB | journal = The Journal of Biological Chemistry | volume = 281 | issue = 39 | pages = 29213–20 | date = September 2006 | pmid = 16877381 | doi = 10.1074/jbc.m600754200 | doi-access = free }}</ref> A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII.<ref name="Soksawatmaekhin 2006" /> Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "''rocking bundle"'' mechanism.<ref name="TCDB" /><ref name="Forrest">{{cite journal | vauthors = Forrest LR, Rudnick G | title = The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters | journal = Physiology | volume = 24 | issue = 6 | pages = 377–86 | date = December 2009 | pmid = 19996368 | doi = 10.1152/physiol.00030.2009 | pmc=3012352}}</ref><ref name="Rudnick 2011">{{cite journal | vauthors = Rudnick G | title = Cytoplasmic permeation pathway of neurotransmitter transporters | journal = Biochemistry | volume = 50 | issue = 35 | pages = 7462–75 | date = September 2011 | pmid = 21774491 | doi = 10.1021/bi200926b | pmc=3164596}}</ref> | |||
| The larger eukaryotic and archaeal proteins possess N- and C-terminal hydrophilic extensions. Some animal proteins, for example, those in the LAT family () including and 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 (), which maintains cellular redox balance and cysteine/glutathione levels <ref name="Sato 2005">{{cite journal|last1=Sato|first1=H|last2=Shiiya|first2=A|last3=Kimata|first3=M|last4=Maebara|first4=K|last5=Tamba|first5=M|last6=Sakakura|first6=Y|last7=Makino|first7=N|last8=Sugiyama|first8=F|last9=Yagami|first9=K|last10=Moriguchi|first10=T|last11=Takahashi|first11=S|last12=Bannai|first12=S|title=Redox imbalance in cystine/glutamate transporter-deficient mice.|journal=Journal of Biological Chemistry|date=Nov 11, 2005|volume=280|issue=45|pages=37423-9|pmid=16144837}}</ref>. They are members of the rBAT family of mammalian proteins (). | |||
| The structure and function of the cadaverine-lysine antiporter, CadB (), and the putrescine-ornithine antiporter, PotE (), in ''E. coli'' have been evaluated using model structures based on the crystal structure of AdiC (), 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.<ref name=TCDB/> | |||
| 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.<ref name=Fang>{{cite journal | vauthors = Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C | title = Structure of a prokaryotic virtual proton pump at 3.2 A resolution | journal = Nature | volume = 460 | issue = 7258 | pages = 1040–3 | date = August 2009 | pmid = 19578361 | doi = 10.1038/nature08201 | pmc=2745212| bibcode = 2009Natur.460.1040F }}</ref> 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, 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<sup>+</sup>-coupled solute transporters: ] (), NCS1 (), ] () and ] ().<ref name=TCDB/><ref name=Fang/> | |||
| Two APC family members, LAT1 and LAT2 (), transport a neurotoxicant, the methylmercury-L-cysteine complex, by ] <ref name=SimWillis>{{cite journal|last1=Simmons-Willis|first1=TA|last2=Koh|first2=AS|last3=Clarkson|first3=TW|last4=Ballatori|first4=N|title=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.|journal=Biochemical Journal|date=October 1, 2002|volume=367|issue=1|pages=239-46|pmid=12117417}}</ref>. | |||
| ===Transport reactions=== | |||
| Transport reactions generally catalyzed by APC superfamily members include:<ref name=TCDB/> | |||
| ==== Solute:proton symport ==== | |||
| Hip1 of S. cerevisiae () has been implicated in heavy metal transport. Distant constituents of the APC superfamily are the AAAP family (), the HAAAP family () and the LCT family (). Some of these proteins exhibit 11 TMSs. Eukaryotic members of this superfamily have been reviewed by Wipf et al. (2002) <ref name=Wipf1>{{cite journal|last1=Wipf|first1=D|last2=Ludewig|first2=U|last3=Tegeder|first3=M|last4=Rentsch|first4=D|last5=Koch|first5=W|last6=Frommer|first6=WB|title=Conservation of amino acid transporters in fungi, plants and animals.|journal=Trends in Biochemical Sciences|date=March 2000|volume=27|issue=3|pages=139-47|pmid=11893511}}</ref> and Fischer et al. (1998) <ref name=Fischer>{{cite journal|last1=Fischer|first1=WN|last2=André|first2=B|last3=Rentsch|first3=D|last4=Krolkiewics|first4=S|last5=Tegeder|first5=M|last6=Breitkreuz|first6=K|last7=Frommer|first7=WB|title=Amino acid transport in plants.|journal=Trends Plant Sci.|date=1998|volume=3|issue=188-195}}</ref>. | |||
| <blockquote>Solute (out) + nH<sup>+</sup> (out) → Solute (in) + nH<sup>+</sup> (in).</blockquote> | |||
| <ref name=TCDB>{{cite web|last1=Saier|first1=MH Jr.|title=2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily|url=http://www.tcdb.org/search/result.php?tc=2.A.3|website=Transporter Classification Database|publisher=Saier Lab Bioinformatics Group}}</ref> | |||
| ==== Solute:solute antiport ==== | |||
| <blockquote>Solute-1 (out) + Solute-2 (in) ⇌ Solute-1 (in) + Solute-2 (out).</blockquote>These reactions may differ for some family members. | |||
| == References == | |||
| {{reflist|2}} | |||
| == Further reading == | |||
| ===Families=== | |||
| {{refbegin}} | |||
| Currently recognized families within the APC Superfamily (with TC numbers in blue) include: <ref name=TCDB /> | |||
| * {{cite journal | vauthors = Chang AB, Lin R, Keith Studley W, Tran CV, Saier MH | title = Phylogeny as a guide to structure and function of membrane transport proteins | journal = Molecular Membrane Biology | volume = 21 | issue = 3 | pages = 171–81 | date = May 2004 | pmid = 15204625 | doi = 10.1080/09687680410001720830 | s2cid = 45284885 }} | |||
| * {{cite journal | vauthors = Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH | title = Expansion of the APC superfamily of secondary carriers | journal = Proteins | volume = 82 | issue = 10 | pages = 2797–811 | date = October 2014 | pmid = 25043943 | pmc = 4177346 | doi = 10.1002/prot.24643 }} | |||
| * {{cite journal | vauthors = Wong FH, Chen JS, Reddy V, Day JL, Shlykov MA, Wakabayashi ST, Saier MH | title = The amino acid-polyamine-organocation superfamily | journal = Journal of Molecular Microbiology and Biotechnology | volume = 22 | issue = 2 | pages = 105–13 | date = 2012 | pmid = 22627175 | doi = 10.1159/000338542 | doi-access = free }} | |||
| * {{cite journal | vauthors = Jack DL, Paulsen IT, Saier MH | title = The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations | journal = Microbiology | volume = 146 | issue = 8 | pages = 1797–814 | date = August 2000 | pmid = 10931886 | doi = 10.1099/00221287-146-8-1797 | doi-access = free }} | |||
| * {{cite journal | vauthors = Kaur J, Olkhova E, Malviya VN, Grell E, Michel H | title = A L-lysine transporter of high stereoselectivity of the amino acid-polyamine-organocation (APC) superfamily: production, functional characterization, and structure modeling | journal = The Journal of Biological Chemistry | volume = 289 | issue = 3 | pages = 1377–87 | date = January 2014 | pmid = 24257746 | pmc = 3894322 | doi = 10.1074/jbc.M113.510743 | doi-access = free }} | |||
| {{refend}} | |||
| {{Portal bar|Biology|border=no}} | |||
| * - The Amino Acid-Polyamine-Organocation (APC) Family | |||
| * - The Betaine/Carnitine/Choline Transporter (BCCT) Family | |||
| * - The Amino Acid/Auxin Permease (AAAP) Family | |||
| * - The Solute:Sodium Symporter (SSS) Family | |||
| * - The Neurotransmitter:Sodium Symporter (NSS) Family | |||
| * - The Alanine or Glycine:Cation Symporter (AGCS) Family | |||
| * - The Branched Chain Amino Acid:Cation Symporter (LIVCS) Family | |||
| * - The Cation-Chloride Cotransporter (CCC) Family | |||
| * - The Anion Exchanger (AE) Family | |||
| * - The Nucleobase:Cation Symporter-1 (NCS1) Family | |||
| * - The Nucleobase/Ascorbate Transporter (NAT) or Nucleobase:Cation Symporter-2 (NCS2) Family | |||
| * - The Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family | |||
| * - The Benzoate:H+ Symporter (BenE) Family | |||
| * - The Sulfate Permease (SulP) Family | |||
| * - The Metal Ion (Mn2+-iron) Transporter (Nramp) Family | |||
| * - The K+ Uptake Permease (KUP) Family | |||
| * - The Putative Peptide Transporter Carbon Starvation CstA (CstA) Family | |||
| * - The Putative Amino Acid Permease (PAAP) Family | |||
| {{CCBYSASource|sourcepath=http://www.tcdb.org/search/result.php?tc=2.A.3|sourcearticle=The Amino Acid-Polyamine-Organocation (APC) Superfamily|revision=699838558}} | |||
| ] | |||
| ==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 <ref name="Soksawatmaekhin 2006">{{cite journal|last1=Soksawatmaekhin|first1=W|last2=Uemura|first2=T|last3=Fukiwake|first3=N|last4=Kashiwagi|first4=K|last5=Igarashi|first5=K|title=Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB.|journal=Journal of Biological Chemistry|date=Sep 29, 2006|volume=281|issue=39|pages=29213-20|pmid=16877381}}</ref>. A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII <ref name="Soksawatmaekhin 2006" />. Based on 3-d structures of APC superfamily members, Rudnick (2011) <ref name=Forrest>{{cite journal|last1=Forrest|first1=L|last2=Rudnick|first2=G|title=The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters.|journal=American Physiological Society|date=December 8, 2009|volume=24|issue=6|pages=377-386|doi=10.1152/physiol.00030.2009}}</ref> <ref name="Rudnick 2011">{{cite journal|last1=Rudnick|first1=G|title=Cytoplasmic permeation pathway of neurotransmitter transporters.|journal=Biochemistry|date=2011|volume=50|issue=35|pages=7462-7475|doi=10.1021/bi200926b}}</ref> has proposed the pathway for transport and suggested a ''rocking bundle mechanism''. <ref name=TCDB/> | |||
| ] | |||
| ] | |||
| 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 <ref name=Shaffer>{{cite journal|last1=Shaffer|first1=PL|last2=Goehring|first2=A|last3=Shankaranarayanan|first3=A|last4=Gouaux|first4=E|title=Structure and mechanism of a Na+-independent amino acid transporter.|journal=Science|date=August 21, 2009|volume=325|issue=5943|pages=1010-4|doi=10.1126/science.1176088|pmid=19608859}}</ref>. The structure contains 12 transmembrane helices, with the first 10 consisting of an inverted structural repeat of 5 transmembrane helices like LeuT (). 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. <ref name=TCDB/> | |||
| The structure and function of the cadaverine-lysine antiporter, CadB (), and the putrescine-ornithine antiporter, PotE (), in E. coli have been evaluated using model structures based on the crystal structure of AdiC (), 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. <ref name=TCDB/> | |||
| 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 <ref name=Fang>{{cite journal|last1=Fang|first1=Y|last2=Jayaram|first2=H|last3=Shane|first3=T|last4=Kolmakova-Partensky|first4=L|last5=Wu|first5=F|last6=Williams|first6=C|last7=Xiong|first7=Y|last8=Miller|first8=C|title=Structure of a prokaryotic virtual proton pump at 3.2 A resolution.|journal=Nature|date=August 20, 2009|volume=460|issue=7258|pages=1040-3|doi=10.1038/nature08201}}</ref>. 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<sup>+</sup>-coupled solute transporters: BCCT (), NCS1 (), SSS () and NSS () <ref name=Fang/>. <ref name=TCDB/> | |||
| ===Transport Reactions=== | |||
| Transport reactions catalyzed by APC family members include: <ref name=TCDB/> | |||
| ::Solute:proton ] | |||
| Solute (out) + nH<sup>+</sup> (out) → Solute (in) + nH<sup>+</sup> (in). | |||
| ::Solute:solute ] | |||
| Solute-1 (out) + Solute-2 (in) ⇌ Solute-1 (in) + Solute-2 (out). | |||
| ==References== | |||
| {{reflist}} | |||
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| Identifiers | |
|---|---|
| Symbol | APC |
| Pfam clan | CL0062 |
| ECOD | 5051.1.1 |
| TCDB | 2.A.3 |
| OPM superfamily | 64 |
The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number (TC # 2.A.3). This superfamily has since been expanded to include eighteen different families.
The most recent families added include the PAAP (Putative Amino Acid Permease), LIVCS (Branched Chain Amino Acid:Cation Symporter), NRAMP (Natural Resistance-Associated Macrophage Protein), CstA (Carbon starvation A protein), KUP (K Uptake Permease), BenE (Benzoate:H Virginia Symporter), and AE (Anion Exchanger). Bioinformatic and phylogenetic analysis is used to continually expand currently existing families and superfamilies.
Other 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) and Fischer et al. (1998).
Families
Currently recognized families within the APC Superfamily (with TC numbers in blue) include:
- 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 (Mn-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
APC proteins in humans
There are several APC proteins expressed in humans, and they are SLC proteins. There are 11 SLC families including APC proteins: SLC4, 5, 6, 7, 11, 12, 23, 26, 32, 36, and 38. The atypical SLC TMEM104 is also clustered to the APC clan.
Structure and function
The topology of the well-characterized human Anion Exchanger 1 (AE1) conforms to a UraA-like topology of 14 TMSs (12 α-helical TMSs and 2 mixed coil/helical TMSs). All functionally characterized members of the APC superfamily use cation symport for substrate accumulation except for some members of the AE family which frequently use anion:anion exchange. All new entries contain the two 5 or 7 TMS repeat units characteristic of the APC superfamily, sometimes with extra TMSs at the ends likely the result of an addition prior to duplication. The CstA family contains the greatest variation in TMSs. New functionally characterized members transport amino acids, peptides, and inorganic anions or cations. Except for anions, these are typical substrates of established APC superfamily members. Active site TMSs are rich in glycyl residues in variable but conserved arrangements.
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. A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII. Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "rocking bundle" mechanism.
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.
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. 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, 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).
Transport reactions
Transport reactions generally catalyzed by APC superfamily members include:
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).
These reactions may differ for some family members.
References
- Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH (October 2014). "Expansion of the APC superfamily of secondary carriers". Proteins. 82 (10): 2797–811. doi:10.1002/prot.24643. PMC 4177346. PMID 25043943.
- ^ Höglund, Pär J.; Nordström, Karl J. V.; Schiöth, Helgi B.; Fredriksson, Robert (April 2011). "The solute carrier families have a remarkably long evolutionary history with the majority of the human families present before divergence of Bilaterian species". Molecular Biology and Evolution. 28 (4): 1531–1541. doi:10.1093/molbev/msq350. ISSN 1537-1719. PMC 3058773. PMID 21186191.
- ^ Perland, Emelie; Fredriksson, Robert (March 2017). "Classification Systems of Secondary Active Transporters". Trends in Pharmacological Sciences. 38 (3): 305–315. doi:10.1016/j.tips.2016.11.008. ISSN 1873-3735. PMID 27939446.
- Wipf D, Ludewig U, Tegeder M, Rentsch D, Koch W, Frommer WB (March 2002). "Conservation of amino acid transporters in fungi, plants and animals". Trends in Biochemical Sciences. 27 (3): 139–47. doi:10.1016/s0968-0004(01)02054-0. PMID 11893511.
- 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): 188–195. Bibcode:1998TPS.....3..188F. doi:10.1016/S1360-1385(98)01231-X.
- ^ Saier, MH Jr. "2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily". Transporter Classification Database. Saier Lab Bioinformatics Group.
- Hediger, Matthias A.; Romero, Michael F.; Peng, Ji-Bin; Rolfs, Andreas; Takanaga, Hitomi; Bruford, Elspeth A. (February 2004). "The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction". Pflügers Archiv: European Journal of Physiology. 447 (5): 465–468. doi:10.1007/s00424-003-1192-y. ISSN 0031-6768. PMID 14624363. S2CID 1866661.
- ^ Soksawatmaekhin W, Uemura T, Fukiwake N, Kashiwagi K, Igarashi K (September 2006). "Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB". The Journal of Biological Chemistry. 281 (39): 29213–20. doi:10.1074/jbc.m600754200. PMID 16877381.
- 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.
- Rudnick G (September 2011). "Cytoplasmic permeation pathway of neurotransmitter transporters". Biochemistry. 50 (35): 7462–75. doi:10.1021/bi200926b. PMC 3164596. PMID 21774491.
- ^ Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C (August 2009). "Structure of a prokaryotic virtual proton pump at 3.2 A resolution". Nature. 460 (7258): 1040–3. Bibcode:2009Natur.460.1040F. doi:10.1038/nature08201. PMC 2745212. PMID 19578361.
Further reading
- Chang AB, Lin R, Keith Studley W, Tran CV, Saier MH (May 2004). "Phylogeny as a guide to structure and function of membrane transport proteins". Molecular Membrane Biology. 21 (3): 171–81. doi:10.1080/09687680410001720830. PMID 15204625. S2CID 45284885.
- Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH (October 2014). "Expansion of the APC superfamily of secondary carriers". Proteins. 82 (10): 2797–811. doi:10.1002/prot.24643. PMC 4177346. PMID 25043943.
- 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.
- 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. doi:10.1099/00221287-146-8-1797. PMID 10931886.
- Kaur J, Olkhova E, Malviya VN, Grell E, Michel H (January 2014). "A L-lysine transporter of high stereoselectivity of the amino acid-polyamine-organocation (APC) superfamily: production, functional characterization, and structure modeling". The Journal of Biological Chemistry. 289 (3): 1377–87. doi:10.1074/jbc.M113.510743. PMC 3894322. PMID 24257746.
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