Encyclopedia of Biophysics

Living Edition
| Editors: Gordon Roberts, Anthony Watts, European Biophysical Societies

Membrane Transport Proteins: The Nucleobase-Cation-Symport-1 Family

  • Georgia F. Papadaki
  • Pikyee Ma
  • Irshad Ahmad
  • Antonio N. Calabrese
  • Stephen A. Baldwin
  • Peter J. F. Henderson
  • George Diallinas
Living reference work entry

Later version available View entry history

DOI: https://doi.org/10.1007/978-3-642-35943-9_684-2



The NCS1 family, designated A.2.39 (Saier et al. 2006, 2009), consists of over 2000 currently sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, yeast, fungi, and some plants (Pantazopoulou and Diallinas 2007; Ren et al. 2007; Ren and Paulsen 2007, 2010). Proteins of the NCS1 family are 419–635 aminoacyl residues long and possess 12 transmembrane α-helices (TMHs). Eukaryotic members of the family are also characterized by extended cytoplasmic N- and C-terminal regions, which include cis-acting elements critical for their subcellular membrane sorting and endocytic turnover (Lauwers et al. 2010; Keener and Babst 2013;...

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  1. Ahmad I (2017) Characterisation of membrane transport proteins of NCS1 and PACE families using biochemical and biophysical techniques. PhD Thesis, University of LeedsGoogle Scholar
  2. Calabrese AN, Jackson SM, Jones LN, Beckstein O, Heinkel F, Gsponer J, Sans M, Kokkinidou M, Pearson AR, Radford SE, Ashcroft AE, Henderson PJF (2017) Topological dissection of the membrane transport protein Mhp1 derived from cysteine accessibility and mass spectrometry. Anal Chem 89:8844–8852CrossRefPubMedPubMedCentralGoogle Scholar
  3. Danielsen S, Kilstrup M, Barilla K, Jochimsen B, Neuhard J (1992) Characterization of the Escherichia coli codBA operon encoding cytosine permease and cytosine deaminase. Mol Microbiol 6:1335–1344CrossRefPubMedGoogle Scholar
  4. Diallinas G (2008) Biochemistry. An almost-complete movie. Science 322:1644–1645CrossRefPubMedGoogle Scholar
  5. Drew D, Boudker O (2016) Shared molecular mechanisms of membrane transporters. Annu Rev Biochem 85:543–572CrossRefPubMedGoogle Scholar
  6. Florent M, Noël T, Ruprich-Robert G, Da Silva B, Fitton-Ouhabi V, Chastin C, Papon N, Chapeland-Leclerc F (2009) Nonsense and missense mutations in FCY2 and FCY1 genes are responsible for flucytosine resistance and flucytosine-fluconazole cross-resistance in clinical isolates of Candida lusitaniae. Antimicrob Agents Chemother 53:2982–2990CrossRefPubMedPubMedCentralGoogle Scholar
  7. Javier Las Heras-Vázquez F, Clemente-Jiménez JM, Martínez-Rodríguez S, Rodríguez-Vico F (2009) Hydantoin racemase: the key enzyme for the production of optically pure α-amino acids, ch12. In: Fessner W-D, Anthonsen T (eds) Modern biocatalysis: stereoselective and environmentally friendly reactions. Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimGoogle Scholar
  8. Kaback HR, Smirnova I, Kasho V, Nie Y, Zhou Y (2011) The alternating access transport mechanism in LacY. J Membr Biol 239:85–93CrossRefPubMedGoogle Scholar
  9. Kazmier K, Sharma S, Islam SM, Roux B, Mchaourab HS (2014) Conformational cycle and ion coupling mechanism of the Na+/hydantoin transporter Mhp1. Proc Natl Acad Sci U S A 111:14752–14757CrossRefPubMedPubMedCentralGoogle Scholar
  10. Keener JM, Babst M (2013) Quality control and substrate-dependent downregulation of the nutrient transporter Fur4. Traffic 14:412–427CrossRefPubMedPubMedCentralGoogle Scholar
  11. Krishnamurthy H, Piscitelli CL, Gouaux E (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459:347–355CrossRefPubMedGoogle Scholar
  12. Krypotou E, Kosti V, Amillis S, Myrianthopoulos V, Mikros E, Diallinas G (2012) Modeling, substrate docking, and mutational analysis identify residues essential for the function and specificity of a eukaryotic purine-cytosine NCS1 transporter. J Biol Chem 287:36792–36803CrossRefPubMedPubMedCentralGoogle Scholar
  13. Krypotou E, Evangelidis T, Bobonis J, Pittis AA, Gabaldón T, Scazzocchio C, Mikros E, Diallinas G (2015) Origin, diversification and substrate specificity in the family of NCS1/FUR transporters. Mol Microbiol 96:927–950CrossRefPubMedGoogle Scholar
  14. Lauwers E, Erpapazoglou Z, Haguenauer-Tsapis R, André B (2010) The ubiquitin code of yeast permease trafficking. Trends Cell Biol 20:196–204CrossRefPubMedGoogle Scholar
  15. Lougiakis N, Gavriil ES, Kairis M, Sioupouli G, Lambrinidis G, Benaki D, Krypotou E, Mikros E, Marakos P, Pouli N, Diallinas G (2016) Design and synthesis of purine analogues as highly specific ligands for FcyB, a ubiquitous fungal nucleobase transporter. Bioorg Med Chem 24:5941–5952CrossRefPubMedGoogle Scholar
  16. Ma P (2010) Structure-activity relationships of membrane proteins; the NCS-1 family of transporters. PhD Thesis, University of LeedsGoogle Scholar
  17. Ma P, Patching SG, Ivanova E, Baldwin JM, Sharples D, Baldwin SA, Henderson PJ (2016) Allantoin transport protein, PucI, from Bacillus subtilis: evolutionary relationships, amplified expression, activity and specificity. Microbiology 162:823–836CrossRefPubMedPubMedCentralGoogle Scholar
  18. Mourad GS, Tippmann-Crosby J, Hunt KA, Gicheru Y, Bade K, Mansfield TA, Schultes NP (2012) Genetic and molecular characterization reveals a unique nucleobase cation symporter 1 in Arabidopsis. FEBS Lett 586:1370–1378CrossRefPubMedGoogle Scholar
  19. Paluszynski JP, Klassen R, Rohe M, Meinhardt F (2006) Various cytosine/adenine permease homologues are involved in the toxicity of 5-fluorocytosine in Saccharomyces cerevisiae. Yeast 23:707–715CrossRefPubMedGoogle Scholar
  20. Pantazopoulou A, Diallinas G (2007) Fungal nucleobase transporters. FEMS Microbiol Rev 31:657–675CrossRefPubMedGoogle Scholar
  21. Papadaki GF, Amillis S, Diallinas G (2017) Substrate specificity of the FurE transporter is determined by cytoplasmic terminal domain interactions. Genetics 207:1387–1400PubMedGoogle Scholar
  22. Rapp M, Schein J, Hunt KA, Nalam V, Mourad GS, Schultes NP (2015) The solute specificity profiles of nucleobase cation symporter 1 (NCS1) from Zea mays and Setaria viridis illustrate functional flexibility. Protoplasma 253:611–623CrossRefPubMedGoogle Scholar
  23. Ren Q, Paulsen IT (2007) Large-scale comparative genomic analyses of cytoplasmic membrane transport systems in prokaryotes. J Mol Microbiol Biotechnol 12:165–179CrossRefPubMedGoogle Scholar
  24. Ren Q, Paulsen IT (2010) TransportDB. http://www.membranetransport.org/
  25. Ren Q, Chen K, Paulsen IT (2007) TransportDB: a comprehensive database resource for cytoplasmic membrane transport systems and outer membrane channels. Nucleic Acids Res 35:D274–D279CrossRefPubMedGoogle Scholar
  26. Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (2002) Comparative genomics of thiamin biosynthesis in procaryotes. J Biol Chem 277:48949–48959CrossRefPubMedGoogle Scholar
  27. Saier MH Jr, Tran CV, Barabote RD (2006) TCDB: the transporter classification database for membrane transport protein analyses and information. Nucleic Acids Res 34:D181–D186CrossRefPubMedGoogle Scholar
  28. Saier MH Jr, Yen MR, Noto K, Tamang DG, Elkan C (2009) The transporter classification database: recent advances. Nucl Acids Res 37:D274–D278CrossRefPubMedGoogle Scholar
  29. Schein JR, Hunt KA, Minton JA, Schultes NP, Mourad GS (2013) The nucleobase cation symporter 1 of Chlamydomonas reinhardtii and that of the evolutionarily distant Arabidopsis thaliana display parallel function and establish a plant-specific solute transport profile. Plant Physiol Biochem 70:52–60CrossRefPubMedGoogle Scholar
  30. Schultz AC, Nygaard P, Saxild HH (2001) Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator. J Bacteriol 183:3293–3302CrossRefPubMedPubMedCentralGoogle Scholar
  31. Shimamura T, Yajima S, O’Reilly J, Rutherford NG, Henderson PJF, Iwata S (2008) Crystallization of the hydantoin transporter Mhp1 from Microbacterium liquefaciens. Acta Crystallog F64:1172–1174Google Scholar
  32. Shimamura T, Weyand S, Beckstein O, Rutherford NG, Hadden JM, Sharples D, Sansom MS, Iwata S, Henderson PJ, Cameron AD (2010) Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. Science 328:470–473CrossRefPubMedPubMedCentralGoogle Scholar
  33. Simmons KJ, Jackson SM, Brueckner F, Patching SG, Beckstein O, Ivanova E, GengT WS, Drew D, Lanigan J, Sharples DJ, Sansom MS, Iwata S, Fishwick CW, Johnson AP, Cameron AD, Henderson PJ (2014) Molecular mechanism of ligand recognition by membrane transport protein, Mhp1. EMBO J 33:1831–1844CrossRefPubMedPubMedCentralGoogle Scholar
  34. Sioupouli G, Lambrinidis G, Mikros E, Amillis S, Diallinas G (2017) Cryptic purine transporters in Aspergillus nidulans reveal the role of specific residues in the evolution of specificity in the NCS1 family. Mol Microbiol 103:319–332CrossRefPubMedGoogle Scholar
  35. Suzuki S, Henderson PJF (2006) The hydantoin transport protein from Microbacterium liquefacien. J Bacteriol 188:3329–3336CrossRefPubMedPubMedCentralGoogle Scholar
  36. Suzuki S, Takenaka Y, Onishi N, Yokozeki K (2005) Molecular cloning and expression of the hyu genes of Microbacterium liquefaciens responsible for the conversion of 5-substituted hydantoins to alpha amino acids, in Escherichia coli. Biosci Biotechnol Biochem 69:1473–1482CrossRefPubMedGoogle Scholar
  37. Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH Jr (2014) Expansion of the APC superfamily of secondary carriers. Proteins 82:2797–2811CrossRefPubMedPubMedCentralGoogle Scholar
  38. Weyand S, Shimamura T, Yajima S, Suzuki S, Mirza O, Krusong K, Carpenter EP, Rutherford NG, Hadden JM, O’Reilly J, Ma P, Saidijam M, Patching SG, Hope RJ, Norbertczak HT, Roach PCJ, Iwata S, Henderson PJF, Cameron AD (2008) Molecular basis of the alternating access model of membrane transport: structure of a nucleobase-cation-symport-1 family transporter. Science 322:709–713CrossRefPubMedPubMedCentralGoogle Scholar
  39. Weyand S, Ma P, Beckstein O, Baldwin J, Jackson S, Suzuki S, Shimamura T, Sansom MSP, Iwata S, Cameron AD, Baldwin SA, Henderson PJF (2010) The nucleobase-cation-symport-1 family of membrane transport proteins. In: Messerschmidt A (ed) Handbook of metalloproteins. Wiley, Chichester, pp 848–864Google Scholar
  40. Wiese A, Mattes R, Syldatk C, Altenbucher J (2001) Organization of genes responsible for the stereospecific conversion of hydantoins to α-amino acids in Arthrobacter aurescens DSM 3747. Arch Microbiol 176:187–196CrossRefPubMedGoogle Scholar
  41. Witz S, Jung B, Fürst S, Möhlmann T (2012) De novo pyrimidine nucleotide synthesis mainly occurs outside of plastids, but a previously undiscovered nucleobase importer provides substrates for the essential salvage pathway in Arabidopsis. Plant Cell 24:1549–1559CrossRefPubMedPubMedCentralGoogle Scholar
  42. Witz S, Panwar P, Schober M, Deppe J, Pasha FA, Lemieux MJ, Möhlmann T (2014) Structure-function relationship of a plant NCS1 member–homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis. PLoS One 9:e91343CrossRefPubMedPubMedCentralGoogle Scholar
  43. Yoo HS, Cunningham TS, Cooper TG (1992) The allantoin and uracil permease gene sequences of Saccharomyces cerevisiae are nearly identical. Yeast 8:997–1006CrossRefPubMedGoogle Scholar

Copyright information

© European Biophysical Societies' Association (EBSA) 2018

Authors and Affiliations

  • Georgia F. Papadaki
    • 1
  • Pikyee Ma
    • 2
    • 3
  • Irshad Ahmad
    • 2
  • Antonio N. Calabrese
    • 2
  • Stephen A. Baldwin
    • 3
  • Peter J. F. Henderson
    • 2
    • 3
  • George Diallinas
    • 1
  1. 1.Department of BiologyNational and Kapodistrian University of AthensPanepistimioupolisGreece
  2. 2.Astbury Centre for Structural Molecular Biology, School of BioMedical SciencesUniversity of LeedsLeedsUK
  3. 3.Astbury Centre for Structural Molecular Biology, Institute of Membrane and Systems BiologyUniversity of LeedsLeedsUK

Section editors and affiliations

  • Peter J. F. Henderson
    • 1
  1. 1.Astbury Centre for Structural Molecular Biology, Institute of Membrane and Systems BiologyUniversity of LeedsLeedsUK