Nucleobase cation symporter-1

Last updated
Permease for cytosine/purines, uracil, thiamine, allantoin
Identifiers
SymbolTransp_cyt_pur
Pfam PF02133
InterPro IPR001248
TCDB 2.A.39
OPM superfamily 64
OPM protein 2x79
CDD cd10323
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The Nucleobase:Cation Symporter-1 (NCS1) Family (TC# 2.A.39) consists of over 1000 currently sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, fungi and plants. These proteins function as transporters for nucleobases including purines and pyrimidines. Members of this family possess twelve transmembrane α-helical spanners (TMSs). At least some of them have been shown to function in uptake by substrate:H+ symport mechanism.

Contents

Phylogeny

The bacterial and yeast proteins are widely divergent and do not cluster closely on the NCS1 family phylogenetic tree. B. subtilis possesses two paralogues of the NCS1 family, and S. cerevisiae has several. Two of the yeast proteins (Dal4 (TC# 2.A.39.3.1) and Fur4 (TC# 2.A.39.3.2)) cluster tightly together. Three other S. cerevisiae proteins, one of which is the thiamin permease, Thi10 (TC# 2.A.39.4.1), and another of which is the nicotinamide riboside transporter, Nrt1 (TC# 2.A.39.4.2), [1] also cluster tightly together. The latter three proteins are likely to be closely related thiamin permease isoforms. The yeast cytosine-purine and vitamin B6 transporters cluster loosely together (24% identity; e-50). [2] The bacterial proteins are derived from several Gram-negative and Gram-positive species. These proteins exhibit limited sequence similarity with the xanthine permease, PbuX (TC# 2.A.39.4.1), of Bacillus subtilis which is a member of the NCS2 family. [3]

Structure and function

Proteins of the NCS1 family are 419-635 amino acyl residues long and possess twelve putative transmembrane α-helical spanners (TMSs). At least some of them have been shown to function in uptake by substrate:H+ symport. In these respects, and with respect to substrate specificity, these proteins resemble the symporters of the NCS2 family, providing further evidence that the two families represent distant constituents of a single superfamily, the APC Superfamily. The two families probably arose by an early gene duplication event that occurred long before divergence of the three major kingdoms of life. It is possible that they are distant constituents of the MFS (2.A.1). [3]

The nucleobase-cation-symport-1 (NCS1) transporters are essential components of salvage pathways for nucleobases and related metabolites. Weyand et al. (2008) reported the 2.85-angstrom resolution structure of the NCS1 benzyl-hydantoin transporter, Mhp1 (TC# 2.A.39.3.6), from Microbacterium liquefaciens. [4] This structure (and related structures) are available through RCSB ( PDB: 2JLN ​, 2X79 ​, 4D1A ​, 4D1B ​, 4D1C ​, 4D1D ​). Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate. [5] Comparisons with the leucine transporter LeuT(Aa) and the galactose transporter vSGLT reveal that the outward- and inward-facing cavities are symmetrically arranged on opposite sides of the membrane. The reciprocal opening and closing of these cavities is synchronized by the inverted repeat helices 3 and 8, providing the structural basis of the alternating access model for membrane transport. [4]

Substrates

NCS1 proteins are H+/Na+ symporters specific for the uptake of purines, pyrimidines and related metabolites. Krypotou et al. 2015 studied the origin, diversification and substrate specificities of fungal NCS1 transporters, suggesting that the two fungal NCS1 subfamilies, Fur and Fcy, and plant homologues, originated through independent horizontal transfers from prokaryotes. [6] Expansion by gene duplication led to functional diversification of fungal NCS1 porters. They characterized all Fur proteins in Aspergillus nidulans. Homology modelling, substrate docking, molecular dynamics and systematic mutational analysis in three Fur transporters with distinct specificities identified residues critical for function and specificity, located within a major substrate binding site, in transmembrane segments TMS1, TMS3, TMS6 and TMS8. They predicted and confirmed that residues determining substrate specificity are located not only in the major substrate binding site, but also in a putative outward-facing selectivity gate. Their evolutionary and structure-function analyses led to the concept that selective channel-like gates may contribute to substrate specificity. [6]

Transport reaction

The generalized transport reaction catalyzed by NCS1 family permeases is: [3]

Nucleobase or Vitamin (out) + H+ (out) → Nucleobase or Vitamin (in) + H+ (in)

See also

Related Research Articles

The galactose permease or GalP found in Escherichia coli is an integral membrane protein involved in the transport of monosaccharides, primarily hexoses, for utilization by E. coli in glycolysis and other metabolic and catabolic pathways (3,4). It is a member of the Major Facilitator Super Family (MFS) and is homologue of the human GLUT1 transporter (4). Below you will find descriptions of the structure, specificity, effects on homeostasis, expression, and regulation of GalP along with examples of several of its homologues.

<span class="mw-page-title-main">Lactose permease</span> Membrane protein

Lactose permease is a membrane protein which is a member of the major facilitator superfamily. Lactose permease can be classified as a symporter, which uses the proton gradient towards the cell to transport β-galactosides such as lactose in the same direction into the cell.

<span class="mw-page-title-main">Betaine transporter</span> Family of transport proteins

The Betaine/Carnitine/Choline Transporter (BCCT) family proteins are found in Gram-negative and Gram-positive bacteria and archaea. The BCCT family members a large group of secondary transporters, the APC superfamily. Their common functional feature is that they all transport molecules with a quaternary ammonium group [R-N (CH3)3]. The BCCT family proteins vary in length between 481 and 706 amino acyl residues and possess 12 putative transmembrane α-helical spanners (TMSs). The x-ray structures reveal two 5 TMS repeats, with the total TMSs being 10. These porters catalyze bidirectional uniport or are energized by pmf-driven or smf-driven proton or sodium ion symport, respectively, or substrate: substrate antiport. Some of these permeases exhibit osmosensory and osmoregulatory properties inherent to their polypeptide chains.

<span class="mw-page-title-main">Sodium-solute symporter</span> Group of transport proteins

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.

Proteins of the Proton-dependent Oligopeptide Transporter (POT) Family are found in animals, plants, yeast, archaea and both Gram-negative and Gram-positive bacteria, and are part of the major facilitator superfamily. The transport of peptides into cells is a well-documented biological phenomenon which is accomplished by specific, energy-dependent transporters found in a number of organisms as diverse as bacteria and humans. The proton-dependent oligopeptide transporter (PTR) family of proteins is distinct from the ABC-type peptide transporters and was uncovered by sequence analyses of a number of recently discovered peptide transport proteins. These proteins that seem to be mainly involved in the intake of small peptides with the concomitant uptake of a proton.

The Formate-Nitrite Transporter (FNT) Family belongs to the Major Intrinsic Protein (MIP) Superfamily. FNT family members have been sequenced from Gram-negative and Gram-positive bacteria, archaea, yeast, plants and lower eukaryotes. The prokaryotic proteins of the FNT family probably function in the transport of the structurally related compounds, formate and nitrite.

The Nucleobase cation symporter-2 (NCS2) family, also called the Nucleobase ascorbate transporter (NAT) family, consists of over 1000 sequenced proteins derived from gram-negative and gram-positive bacteria, archaea, fungi, plants and animals. The NCS2/NAT family is a member of the APC Superfamily of secondary carriers. Of the five known families of transporters that act on nucleobases, NCS2/NAT is the only one that is most widespread. Many functionally characterized members are specific for nucleobases including both purines and pyrimidines, but others are purine-specific. However, two closely related rat/human members of the family, SVCT1 and SVCT2, localized to different tissues of the body, co-transport L-ascorbate (vitamin C) and Na+ with a high degree of specificity and high affinity for the vitamin. Clustering of NCS2/NAT family members on the phylogenetic tree is complex, with bacterial proteins and eukaryotic proteins each falling into at least three distinct clusters. The plant and animal proteins cluster loosely together, but the fungal proteins branch from one of the three bacterial clusters forming a tighter grouping. E. coli possesses four distantly related paralogous members of the NCS2 family.

Cation diffusion facilitators (CDFs) are transmembrane proteins that provide tolerance of cells to divalent metal ions, such as cadmium, zinc, and cobalt. These proteins are considered to be efflux pumps that remove these divalent metal ions from cells. However, some members of the CDF superfamily are implicated in ion uptake. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. The Cation Diffusion Facilitator (CDF) Superfamily includes the following families:

Proteins currently known to belong to the Ni2+-Co2+ Transporter (NiCoT) family (TC# 2.A.52) can be found in organisms ranging from Gram-negative and Gram-positive bacteria to archaea and some eukaryotes. Members of this family catalyze uptake of Ni2+ and/or Co2+ in a proton motive force-dependent process.

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. This superfamily has since been expanded to include eighteen different families.

The Amino Acid-Polyamine-Organocation (APC) Family of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters. They occur in bacteria, archaea, fungi, unicellular eukaryotic protists, slime molds, plants and animals. 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. The APC Superfamily was established to encompass a wider range of homologues.

Members of the Alanine or Glycine:Cation Symporter (AGCS) Family (TC# 2.A.25) transport alanine and/or glycine in symport with Na+ and or H+.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

The Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family is a member of the large Amino Acid-Polyamine-OrganoCation (APC) Superfamily of secondary carrier proteins. Members of the HAAAP family all function in amino acid uptake. Homologues are present in many Gram-negative and Gram-positive bacteria, with at least one member classified from archaea .

<span class="mw-page-title-main">Natural resistance-associated macrophage protein</span> Family of transport proteins

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

The potassium (K+) uptake permease (KUP) family (TC# 2.A.72) is a member of the APC superfamily of secondary carriers. Proteins of the KUP/HAK/KT family include the KUP (TrkD) protein of E. coli and homologues in both Gram-positive and Gram-negative bacteria. High affinity (20 μM) K+ uptake systems (Hak1, TC# 2.A.72.2.1) of the yeast Debaryomyces occidentalis as well as the fungus, Neurospora crassa, and several homologues in plants have been characterized. Arabidopsis thaliana and other plants possess multiple KUP family paralogues. While many plant proteins cluster tightly together, the Hak1 proteins from yeast as well as the two Gram-positive and Gram-negative bacterial proteins are distantly related on the phylogenetic tree for the KUP family. All currently classified members of the KUP family can be found in the Transporter Classification Database.

The Citrate-Mg2+:H+ (CitM) / Citrate-Ca2+:H+ (CitH) Symporter (CitMHS) Family (TC# 2.A.11) is a family of transport proteins belonging to the Ion transporter superfamily. Members of this family are found in Gram-positive and Gram-negative bacteria, archaea and possibly eukaryotes. These proteins all probably arose by an internal gene duplication event. Lensbouer & Doyle (2010) have reviewed these systems, classifying the porters with three superfamilies, according to ion-preference:

The inorganic phosphate transporter (PiT) family is a group of carrier proteins derived from Gram-negative and Gram-positive bacteria, archaea, and eukaryotes.

The K+Transporter (Trk) Family is a member of the voltage-gated ion channel (VIC) superfamily. The proteins of the Trk family are derived from Gram-negative and Gram-positive bacteria, yeast and plants.

The Glycoside-Pentoside-Hexuronide (GPH):Cation Symporter Family is part of the major facilitator superfamily and catalyzes uptake of sugars (mostly, but not exclusively, glycosides) in symport with a monovalent cation (H+ or Na+). The various members of the family have been reported to use Na+, H+ or Li, Na+ or Li+, or all three cations as the symported cation.

References

  1. ↑ Belenky PA, Moga TG, Brenner C (March 2008). "Saccharomyces cerevisiae YOR071C encodes the high affinity nicotinamide riboside transporter Nrt1". The Journal of Biological Chemistry. 283 (13): 8075–9. doi: 10.1074/jbc.C800021200 . PMID   18258590.
  2. ↑ Stolz J, Vielreicher M (May 2003). "Tpn1p, the plasma membrane vitamin B6 transporter of Saccharomyces cerevisiae". The Journal of Biological Chemistry. 278 (21): 18990–6. doi: 10.1074/jbc.M300949200 . PMID   12649274.
  3. 1 2 3 Saier, MH Jr. "2.A.39 The Nucleobase:Cation Symporter-1 (NCS1) Family". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
  4. 1 2 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 PC, Iwata S, Henderson PJ, Cameron AD (October 2008). "Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter". Science. 322 (5902): 709–13. Bibcode:2008Sci...322..709W. doi:10.1126/science.1164440. PMC   2885439 . PMID   18927357.
  5. ↑ Kazmier K, Sharma S, Islam SM, Roux B, Mchaourab HS (October 2014). "Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1". Proceedings of the National Academy of Sciences of the United States of America. 111 (41): 14752–7. Bibcode:2014PNAS..11114752K. doi: 10.1073/pnas.1410431111 . PMC   4205665 . PMID   25267652.
  6. 1 2 Krypotou E, Evangelidis T, Bobonis J, Pittis AA, Gabaldón T, Scazzocchio C, Mikros E, Diallinas G (June 2015). "Origin, diversification and substrate specificity in the family of NCS1/FUR transporters". Molecular Microbiology. 96 (5): 927–50. doi: 10.1111/mmi.12982 . PMID   25712422. S2CID   23523861.
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