Summary: Glyceraldehyde 3-phosphate dehydrogenase, C-terminal domain
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Glyceraldehyde 3-phosphate dehydrogenase Edit Wikipedia article
|, GAPD, G3PD, HEL-S-162eP, glyceraldehyde-3-phosphate dehydrogenase|
|Glyceraldehyde 3-phosphate dehydrogenase, NAD binding domain|
determinants of enzyme thermostability observed in the molecular structure of thermus aquaticus d-glyceraldehyde-3-phosphate dehydrogenase at 2.5 angstroms resolution
|Glyceraldehyde 3-phosphate dehydrogenase, C-terminal domain|
crystal structure of glyceraldehyde-3-phosphate dehydrogenase from pyrococcus horikoshii ot3
Glyceraldehyde 3-phosphate dehydrogenase (abbreviated as GAPDH or less commonly as G3PDH) (EC 22.214.171.124) is an enzyme of ~37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long established metabolic function, GAPDH has recently been implicated in several non-metabolic processes, including transcription activation, initiation of apoptosis, ER to Golgi vesicle shuttling, and fast axonal, or axoplasmic transport. In sperm, a testis-specific isoenzyme GAPDHS is expressed.
- 1 Structure
- 2 Reaction
- 3 Function
- 4 Use as loading control
- 5 Cellular distribution
- 6 Clinical significance
- 7 Interactions
- 8 Interactive pathway map
- 9 References
- 10 Further reading
Under normal cellular conditions, cytoplasmic GAPDH exists primarily as a tetramer. This form is composed of four identical 37-kDa subunits containing a single catalytic thiol group each and critical to the enzyme's catalytic function. Nuclear GAPDH has increased isoelectric point (pI) of pH 8.3–8.7. Of note, the cysteine residue C152 in the enzyme's active site is required for the induction of apoptosis by oxidative stress. Notably, post-translational modifications of cytoplasmic GAPDH contribute to its functions outside of glycolysis.
|glyceraldehyde 3-phosphate||glyceraldehyde phosphate dehydrogenase||D-glycerate 1,3-bisphosphate|
|NAD+ +Pi||NADH + H+|
|NAD+ +Pi||NADH + H+|
Two-step conversion of G3P
The first reaction is the oxidation of glyceraldehyde 3-phosphate (G3P) at the position-1 (in the diagram it is shown as the 4th carbon from glycolysis), in which an aldehyde is converted into a carboxylic acid (ΔG°'=-50 kJ/mol (−12kcal/mol)) and NAD+ is simultaneously reduced endergonically to NADH.
The energy released by this highly exergonic oxidation reaction drives the endergonic second reaction (ΔG°'=+50 kJ/mol (+12kcal/mol)), in which a molecule of inorganic phosphate is transferred to the GAP intermediate to form a product with high phosphoryl-transfer potential: 1,3-bisphosphoglycerate (1,3-BPG).
This is an example of phosphorylation coupled to oxidation, and the overall reaction is somewhat endergonic (ΔG°'=+6.3 kJ/mol (+1.5)). Energy coupling here is made possible by GAPDH.
GAPDH uses covalent catalysis and general base catalysis to decrease the very large and positive activation energy of the second step of this reaction. First, a cysteine residue in the active site of GAPDH attacks the carbonyl group of GAP, creating a hemithioacetal intermediate (covalent catalysis). Next, an adjacent, tightly bound molecule of NAD+ accepts a hydride ion from GAP, forming NADH while GAP is simultaneously oxidized to a thioester in a concerted series of steps. This thioester species is much higher in energy than the carboxylic acid species that would result in the absence of GAPDH (the carboxylic acid species is so low in energy that the energy barrier for the second step of the reaction (phosphorylation) would be too high, and the reaction, therefore, too slow and equilibrium too unfavorable for a living organism). Donation of the hydride ion by the hemithioacetal is facilitated by its deprotonation by a histidine residue in the enzyme's active site (general base catalysis). Deprotonation encourages the reformation of the carbonyl group in the thioester intermediate and ejection of the hydride ion. NADH leaves the active site and is replaced by another molecule of NAD+, the positive charge of which stabilizes the negatively charged carbonyl oxygen in the transition state of the next and ultimate step. Finally, a molecule of inorganic phosphate attacks the thioester and forms a tetrahedral intermediate, which then collapses to release 1,3-bisphosphoglycerate, and the thiol group of the enzyme's cysteine residue.
As its name indicates, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyses the conversion of glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate. This is the 6th step in the glycolytic breakdown of glucose, an important pathway of energy and carbon molecule supply which takes place in the cytosol of eukaryotic cells. The conversion occurs in two coupled steps. The first is favourable and allows the second unfavourable step to occur.
Transcription and apoptosis
GAPDH can itself activate transcription. The OCA-S transcriptional coactivator complex contains GAPDH and lactate dehydrogenase, two proteins previously only thought to be involved in metabolism. GAPDH moves between the cytosol and the nucleus and may thus link the metabolic state to gene transcription.
In 2005, Hara et al. showed that GAPDH initiates apoptosis. This is not a third function, but can be seen as an activity mediated by GAPDH binding to DNA like in transcription activation, discussed above. The study demonstrated that GAPDH is S-nitrosylated by NO in response to cell stress, which causes it to bind to the protein SIAH1, a ubiquitin ligase. The complex moves into the nucleus where Siah1 targets nuclear proteins for degradation, thus initiating controlled cell shutdown. In subsequent study the group demonstrated that deprenyl, which has been used clinically to treat Parkinson's disease, strongly reduces the apoptotic action of GAPDH by preventing its S-nitrosylation and might thus be used as a drug.
GAPDH acts as reversible metabolic switch under oxidative stress. When cells are exposed to oxidants, they need excessive amounts of the antioxidant cofactor NADPH. In the cytosol, NADPH is reduced from NADP+ by several enzymes, three of them catalyze the first steps of the Pentose phosphate pathway. Oxidant-treatments cause an inactivation of GAPDH. This inactivation re-routes temporally the metabolic flux from glycolysis to the Pentose Phosphate Pathway, allowing the cell to generate more NADPH. Under stress conditions, NADPH is needed by some antioxidant-systems including glutaredoxin and thioredoxin as well as being essential for the recycling of gluthathione.
ER to Golgi transport
GAPDH also appears to be involved in the vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus which is part of shipping route for secreted proteins. It was found that GAPDH is recruited by rab2 to the vesicular-tubular clusters of the ER where it helps to form COP 1 vesicles. GAPDH is activated via tyrosine phosphorylation by Src.
GAPDH, like many other enzymes, has multiple functions. In addition to catalysing the 6th step of glycolysis, recent evidence implicates GAPDH in other cellular processes.GAPDH has been described to exhibit higher order multifunctionality in the context of maintaining cellular iron homeostasis. This came as a surprise to researchers but it makes evolutionary sense to re-use and adapt existing proteins instead of evolving a novel protein from scratch.
Use as loading control
Because the GAPDH gene is often stably and constitutively expressed at high levels in most tissues and cells, it is considered a housekeeping gene. For this reason, GAPDH is commonly used by biological researchers as a loading control for western blot and as a control for qPCR. However, researchers have reported different regulation of GAPDH under specific conditions. For example, the transcription factor MZF-1 has been shown to regulate the GAPDH gene. Therefore, the use of GAPDH as loading control has to be considered carefully.
All steps of glycolysis take place in the cytosol and so does the reaction catalysed by GAPDH. In red blood cells, GAPDH and several other glycolytic enzymes assemble in complexes on the inside of the cell membrane. The process appears to be regulated by phosphorylation and oxygenation. Bringing several glycolytic enzymes close to each other is expected to greatly increase the overall speed of glucose breakdown. Recent studies have also revealed that GAPDH is expressed in an iron dependent fashion on the exterior of the cell membrane a where it plays a role in maintenance of cellular iron homeostasis.
GAPDH is overexpressed in multiple human cancers, such as cutaneous melanoma, and its expression is positively correlated with tumor progression. Its glycolytic and antiapoptotic functions contribute to proliferation and protection of tumor cells, promoting tumorigenesis. Notably, GAPDH protects against telomere shortening induced by chemotherapeutic drugs that stimulate the sphingolipid ceramide. Meanwhile, conditions like oxidative stress impair GAPDH function, leading to cellular aging and death. Moreover, depletion of GAPDH has managed to induce senescence in tumor cells, thus presenting a novel therapeutic strategy for controlling tumor growth.
GAPDH has been implicated in several neurodegenerative diseases and disorders, largely through interactions with other proteins specific to that disease or disorder. These interactions may affect not only energy metabolism but also other GAPDH functions. For example, GAPDH interactions with beta-amyloid precursor protein (betaAPP) could interfere with its function regarding the cytoskeleton or membrane transport, while interactions with huntingtin could interfere with its function regarding apoptosis, nuclear tRNA transport, DNA replication, and DNA repair. In addition, nuclear translocation of GAPDH has been reported in Parkinson's disease (PD), and several anti-apoptotic PD drugs, such as rasagiline, function by preventing the nuclear translocation of GAPDH. It is proposed that hypometabolism may be one contributor to PD, but the exact mechanisms underlying GAPDH involvement in neurodegenerative disease remains to be clarified. The SNP rs3741916 in the 5' UTR of the GAPDH gene may be associated with late onset Alzheimer's disease.
Protein binding partners
GAPDH participates in a number of biological functions through its protein–protein interactions with:
- tubulin to facilitate microtubule bundling;
- actin to facilitate actin polymerization;
- VDAC1 to induce mitochondrial membrane permeabilization (MMP) and apoptosis;
- Inositol 1,4,5-trisphosphate receptor to regulate intracellular Ca2+ signaling;
- Oct-1 to form the coactivator complex OCA-S, which is required for histone H2B synthesis during S phase of the cell cycle;
- p22 to aid microtubule organization;
- Rab2 to facilitate endoplasmic reticulum (ER)–golgi transport;
- Transferrin on the surface of diverse cells and in extracellular fluid;
- Lactate dehydrogenase;
- Apurinic/apyrimidinic endonuclease (APE1), thus converting oxidized APE1 to its reduced form, to restart its endonuclease activity;
- Promyelocytic leukaemia protein (PML) in an RNA-dependent fashion;
- Rheb to sequester the GTPase during low glucose conditions;
- Siah1 to form a complex that translocates to the nucleus, where it ubiquitinates and degrades nuclear proteins during nitrosative stress conditions;
- GAPDH's competitor of Siah protein enhances life (GOSPEL) to block GAPDH interaction with Siah1 and, thus, cell death in response to oxidative stress;
- p300/CREB binding protein (CBP), which acetylates GAPDH and, in turn, enhances the acetylation of additional apoptotic targets;
- skeletal muscle-specific Ca2+/calmodulin-dependent protein kinase;
- Beta-amyloid precursor protein (betaAPP);
- GAPDH can self-associate into homotypic oligomers/aggregates
Nucleic acid binding partners
GAPDH binds to single-stranded RNA and DNA and a number of nucleic acid binding partners have been identified:
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- GRCh38: Ensembl release 89: ENSG00000111640 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000057666 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, Zamzami N, Jan G, Kroemer G, Brenner C (April 2007). "GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization". Oncogene. 26 (18): 2606–20. doi:10.1038/sj.onc.1210074. PMID 17072346.
- Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, Marco S, Saudou F (January 2013). "Vesicular glycolysis provides on-board energy for fast axonal transport". Cell. 152 (3): 479–91. doi:10.1016/j.cell.2012.12.029. PMID 23374344.
- Tristan C, Shahani N, Sedlak TW, Sawa A (February 2011). "The diverse functions of GAPDH: views from different subcellular compartments". Cellular Signalling. 23 (2): 317–23. doi:10.1016/j.cellsig.2010.08.003. PMC . PMID 20727968.
- Nicholls C, Li H, Liu JP (August 2012). "GAPDH: a common enzyme with uncommon functions". Clinical and Experimental Pharmacology & Physiology. 39 (8): 674–9. doi:10.1111/j.1440-1681.2011.05599.x. PMID 21895736.
- Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC . PMID 22182754.
- Zheng L, Roeder RG, Luo Y (July 2003). "S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component". Cell. 114 (2): 255–66. doi:10.1016/S0092-8674(03)00552-X. PMID 12887926.
- Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A (July 2005). "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding". Nature Cell Biology. 7 (7): 665–74. doi:10.1038/ncb1268. PMID 15951807.
- Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, Snyder SH (March 2006). "Neuroprotection by pharmacologic blockade of the GAPDH death cascade". Proceedings of the National Academy of Sciences of the United States of America. 103 (10): 3887–9. doi:10.1073/pnas.0511321103. PMC . PMID 16505364.
- Agarwal AR, Zhao L, Sancheti H, Sundar IK, Rahman I, Cadenas E (November 2012). "Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs". American Journal of Physiology. Lung Cellular and Molecular Physiology. 303 (10): L889–98. doi:10.1152/ajplung.00219.2012. PMID 23064950.
- Ralser M, Wamelink MM, Kowald A, Gerisch B, Heeren G, Struys EA, Klipp E, Jakobs C, Breitenbach M, Lehrach H, Krobitsch S (2007). "Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress". Journal of Biology. 6 (4): 10. doi:10.1186/jbiol61. PMC . PMID 18154684.
- Tisdale EJ, Artalejo CR (June 2007). "A GAPDH mutant defective in Src-dependent tyrosine phosphorylation impedes Rab2-mediated events". Traffic. 8 (6): 733–41. doi:10.1111/j.1600-0854.2007.00569.x. PMC . PMID 17488287.
- Boradia VM, Raje M, Raje CI (December 2014). "Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH)". Biochemical Society Transactions. 42 (6): 1796–801. doi:10.1042/BST20140220. PMID 25399609.
- Barber RD, Harmer DW, Coleman RA, Clark BJ (May 2005). "GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues". Physiological Genomics. 21 (3): 389–95. doi:10.1152/physiolgenomics.00025.2005. PMID 15769908.
- Piszczatowski RT, Rafferty BJ, Rozado A, Tobak S, Lents NH (August 2014). "The glyceraldehyde 3-phosphate dehydrogenase gene (GAPDH) is regulated by myeloid zinc finger 1 (MZF-1) and is induced by calcitriol". Biochemical and Biophysical Research Communications. 451 (1): 137–41. doi:10.1016/j.bbrc.2014.07.082. PMID 25065746.
- Campanella ME, Chu H, Low PS (February 2005). "Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane". Proceedings of the National Academy of Sciences of the United States of America. 102 (7): 2402–7. doi:10.1073/pnas.0409741102. PMC . PMID 15701694.
- Sirover MA (December 2014). "Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity". The International Journal of Biochemistry & Cell Biology. 57: 20–6. doi:10.1016/j.biocel.2014.09.026. PMC . PMID 25286305.
- Kumar S, Sheokand N, Mhadeshwar MA, Raje CI, Raje M (January 2012). "Characterization of glyceraldehyde-3-phosphate dehydrogenase as a novel transferrin receptor". The International Journal of Biochemistry & Cell Biology. 44 (1): 189–99. doi:10.1016/j.biocel.2011.10.016. PMID 22062951.
- Ramos D, Pellín-Carcelén A, Agustí J, Murgui A, Jordá E, Pellín A, Monteagudo C (January 2015). "Deregulation of glyceraldehyde-3-phosphate dehydrogenase expression during tumor progression of human cutaneous melanoma". Anticancer Research. 35 (1): 439–44. PMID 25550585.
- Wang D, Moothart DR, Lowy DR, Qian X (2013). "The expression of glyceraldehyde-3-phosphate dehydrogenase associated cell cycle (GACC) genes correlates with cancer stage and poor survival in patients with solid tumors". PLOS ONE. 8 (4): e61262. doi:10.1371/journal.pone.0061262. PMC . PMID 23620736.
- Phadke M, Krynetskaia N, Mishra A, Krynetskiy E (July 2011). "Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells". Biochemical and Biophysical Research Communications. 411 (2): 409–15. doi:10.1016/j.bbrc.2011.06.165. PMC . PMID 21749859.
- Mazzola JL, Sirover MA (October 2002). "Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders?". Neurotoxicology. 23 (4–5): 603–9. doi:10.1016/s0161-813x(02)00062-1. PMID 12428732.
- Allen M, Cox C, Belbin O, Ma L, Bisceglio GD, Wilcox SL, Howell CC, Hunter TA, Culley O, Walker LP, Carrasquillo MM, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG, Ertekin-Taner N (January 2012). "Association and heterogeneity at the GAPDH locus in Alzheimer's disease". Neurobiology of Aging. 33 (1): 203.e25–33. doi:10.1016/j.neurobiolaging.2010.08.002. PMC . PMID 20864222.
- Raje CI, Kumar S, Harle A, Nanda JS, Raje M (February 2007). "The macrophage cell surface glyceraldehyde-3-phosphate dehydrogenase is a novel transferrin receptor". The Journal of Biological Chemistry. 282 (5): 3252–61. doi:10.1074/jbc.M608328200. PMID 17121833.
- Secreted multifunctional Glyceraldehyde-3-phosphate dehydrogenase sequesters lactoferrin and iron into cells via a non-canonical pathway. Anoop S. Chauhan, Pooja Rawat, Himanshu Malhotra, Navdeep Sheokand, Manoj Kumar, Anil Patidar, Surbhi Chaudhary, Priyanka Jakhar, Chaaya I. Raje and Manoj Raje Scientific Reports 5, 18465; doi:10.1038/srep18465 (2015)
- Voet D, Voet JG (2010). Biochemistry. New York: Wiley. ISBN 0-470-57095-4.
- Stryer L, Berg JM, Tymoczko JL (2002). Biochemistry, Fifth Edition & Lecture Notebook. San Francisco: W. H. Freeman. ISBN 0-7167-9804-2.
- diagram of the GAPDH reaction mechanism from Lodish MCB at NCBI bookshelf
- similar diagram from Alberts The Cell at NCBI bookshelf
NADH + H+
NADH + H+
2 × Pyruvate
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.
Glyceraldehyde 3-phosphate dehydrogenase, C-terminal domain Provide feedback
GAPDH is a tetrameric NAD-binding enzyme involved in glycolysis and glyconeogenesis. C-terminal domain is a mixed alpha/antiparallel beta fold.
Kim H, Feil IK, Verlinde CL, Petra PH, Hol WG; , Biochemistry 1995;34:14975-14986.: Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site. PUBMED:7578111 EPMC:7578111
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR020829
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays an important role in glycolysis and gluconeogenesis [PUBMED:2716055] by reversibly catalysing the oxidation and phosphorylation of D-glyceraldehyde-3-phosphate to 1,3-diphospho-glycerate. The enzyme exists as a tetramer of identical subunits, each containing 2 conserved functional domains: an NAD-binding domain, and a highly conserved catalytic domain [PUBMED:6303388]. The enzyme has been found to bind to actin and tropomyosin, and may thus have a role in cytoskeleton assembly. Alternatively, the cytoskeleton may provide a framework for precise positioning of the glycolytic enzymes, thus permitting efficient passage of metabolites from enzyme to enzyme [PUBMED:6303388].
GAPDH displays diverse non-glycolytic functions as well, its role depending upon its subcellular location. For instance, the translocation of GAPDH to the nucleus acts as a signalling mechanism for programmed cell death, or apoptosis [PUBMED:10740219]. The accumulation of GAPDH within the nucleus is involved in the induction of apoptosis, where GAPDH functions in the activation of transcription. The presence of GAPDH is associated with the synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH itself.
GAPDH has been implicated in certain neurological diseases: GAPDH is able to bind to the gene products from neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease and Machado-Joseph disease through stretches encoded by their CAG repeats. Abnormal neuronal apoptosis is associated with these diseases. Propargylamines such as deprenyl increase neuronal survival by interfering with apoptosis signalling pathways via their binding to GAPDH, which decreases the synthesis of pro-apoptotic proteins [PUBMED:12721812].
This entry represents the C-terminal domain which is a mixed alpha/antiparallel beta fold.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor (GO:0016620)|
|Biological process||oxidation-reduction process (GO:0055114)|
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This clan contains the C terminal domains of dehydrogenase enzymes involved in the biosynthesis of arginine, aspartate and aspartate derived amino acids. It also contains the C terminal domain of GAPDH, a dehydrogenase involved in glycolysis and gluconeogenesis.
The clan contains the following 2 members:Gp_dh_C Semialdhyde_dhC
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|Author:||Eddy SR, Griffiths-Jones SR|
|Number in seed:||50|
|Number in full:||9364|
|Average length of the domain:||152.80 aa|
|Average identity of full alignment:||46 %|
|Average coverage of the sequence by the domain:||44.83 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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Colouring and labels
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.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
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.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 5 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Gp_dh_C domain has been found. There are 474 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 sequence.
Loading structure mapping...