Summary: Permease for cytosine/purines, uracil, thiamine, allantoin
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Nucleobase cation symporter-1 Edit Wikipedia article
|Permease for cytosine/purines, uracil, thiamine, allantoin|
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.
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), 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). 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.
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).
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. This structure (and related structures) are available through RCSB ( , , , , , ). 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. 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.
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. 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.
The generalized transport reaction catalyzed by NCS1 family permeases is:
- Nucleobase or Vitamin (out) + H+ (out) → Nucleobase or Vitamin (in) + H+ (in)
- Belenky, Peter A.; Moga, Tiberiu G.; Brenner, Charles (2008-03-28). "Saccharomyces cerevisiae YOR071C encodes the high affinity nicotinamide riboside transporter Nrt1". The Journal of Biological Chemistry 283 (13): 8075–8079. doi:10.1074/jbc.C800021200. ISSN 0021-9258. PMID 18258590.
- Stolz, Jürgen; Vielreicher, Martin (2003-05-23). "Tpn1p, the plasma membrane vitamin B6 transporter of Saccharomyces cerevisiae". The Journal of Biological Chemistry 278 (21): 18990–18996. doi:10.1074/jbc.M300949200. ISSN 0021-9258. PMID 12649274.
- Saier, MH Jr. "2.A.39 The Nucleobase:Cation Symporter-1 (NCS1) Family". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
- Weyand, Simone; Shimamura, Tatsuro; Yajima, Shunsuke; Suzuki, Shun'ichi; Mirza, Osman; Krusong, Kuakarun; Carpenter, Elisabeth P.; Rutherford, Nicholas G.; Hadden, Jonathan M. (2008-10-31). "Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter". Science (New York, N.Y.) 322 (5902): 709–713. doi:10.1126/science.1164440. ISSN 1095-9203. PMC 2885439. PMID 18927357.
- Kazmier, Kelli; Sharma, Shruti; Islam, Shahidul M.; Roux, Benoît; Mchaourab, Hassane S. (2014-10-14). "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): 14752–14757. doi:10.1073/pnas.1410431111. ISSN 1091-6490. PMC 4205665. PMID 25267652.
- Krypotou, Emilia; Evangelidis, Thomas; Bobonis, Jacob; Pittis, Alexandros A.; Gabaldón, Toni; Scazzocchio, Claudio; Mikros, Emmanuel; Diallinas, George (2015-06-01). "Origin, diversification and substrate specificity in the family of NCS1/FUR transporters". Molecular Microbiology 96 (5): 927–950. doi:10.1111/mmi.12982. ISSN 1365-2958. PMID 25712422.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Permease for cytosine/purines, uracil, thiamine, allantoin Provide feedback
No Pfam abstract.
Vickers MF, Yao SY, Baldwin SA, Young JD, Cass CE;, J Biol Chem. 2000;275:25931-25938.: Nucleoside transporter proteins of Saccharomyces cerevisiae. Demonstration of a transporter (FUI1) with high uridine selectivity in plasma membranes and a transporter (FUN26) with broad nucleoside selectivity in intracellular membranes. PUBMED:10827169 EPMC:10827169
Danielsen S, Kilstrup M, Barilla K, Jochimsen B, Neuhard J;, Mol Microbiol. 1992;6:1335-1344.: Characterization of the Escherichia coli codBA operon encoding cytosine permease and cytosine deaminase. PUBMED:1640834 EPMC:1640834
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001248
This entry represents the purine-cytosine permease family, whose members include allantoin permease Dal4 [PUBMED:1293888], nicotinamide riboside transporter 1 (Nrt1) [PUBMED:18258590], purine-cytosine permease Fcy2/21/22 [PUBMED:9092500], thiamine transporter Thi7/Thi72 [PUBMED:9358046], uracil permease Fur4 [PUBMED:9829833], uridine permease Fui1 [PUBMED:16854981] and vitamin B6 transporter Tpn1 [PUBMED:12649274] from budding yeasts. This entry also includes cytosine permeases codB from E. coli [PUBMED:1640834] and purine-uracil permease AtNCS1 from Arabidopsis [PUBMED:24621654].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Molecular function||transporter activity (GO:0005215)|
|Biological process||transmembrane transport (GO:0055085)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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This large superfamily contains a variety of transporters including amino acid permeases that according to TCDB belong to the APC (Amino acid-Polyamine-organoCation) superfamily.
The clan contains the following 20 members:AA_permease AA_permease_2 AA_permease_C Aa_trans BCCT BenE Branch_AA_trans CstA HCO3_cotransp K_trans MFS_MOT1 Na_Ala_symp Nramp SNF Spore_permease SSF Sulfate_transp Transp_cyt_pur Trp_Tyr_perm Xan_ur_permease
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Author:||Mian N, Bateman A|
|Number in seed:||14|
|Number in full:||3961|
|Average length of the domain:||403.30 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||81.86 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Transp_cyt_pur domain has been found. There are 6 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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