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Pyruvate carboxylase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|Locus||Chr. 11 q11-q13.1|
It is an important anaplerotic reaction that creates oxaloacetate from pyruvate. The enzyme is a mitochondrial protein containing a biotin prosthetic group, requiring magnesium or manganese and acetyl CoA.
Pyruvate carboxylase was first discovered in 1959 at Western Reserve University by M. F. Utter and D. B. Keech. Since then it has been found in a wide variety of prokaryotes and eukaryotes including fungi, bacteria, plants, and animals. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Oxaloacetate produced by PC is an important intermediate, which is used in these biosynthetic pathways. In mammals, PC is expressed in a tissue-specific manner, with its activity found to be highest in the liver and kidney (gluconeogenic tissues), in adipose tissue and lactating mammary gland (lipogenic tissues), and in pancreatic islets. Activity is moderate in brain, heart and adrenal gland, and least in white blood cells and skin fibroblasts.
Structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and gasa sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains a single biotin moiety acting as a swinging arm to transport carbon dioxide to the catalytic site that is formed at the interface between adjacent monomers. Each subunit of the functional tetramer contains four domains: the biotin carboxylation (BC) domain, the transcarboxylation (CT) domain, the biotin carboxyl carrier (BCCP) domain and the recently termed PC tetramerization (PT) domain. From the two most complete crystal structures available, an asymmetric and symmetric form of the protein have been visualized. The Staphylococcus aureus tetramer in complex with the activator Coenzyme A is highly symmetric, possessing 222 symmetry, and has been confirmed by Cryo-EM studies. In contrast the Rhizobium etli, tetramer in complex with ethyl-CoA, a non-hydrolyzable analog of Acetyl-CoA, possesses only one line of symmetry.
Pyruvate carboxylase uses a covalently attached Biotin cofactor which is used to catalyze the ATP– dependent carboxylation of pyruvate to oxaloacetate in two steps. Biotin is initially carboxylated at the BC active site by ATP and bicarbonate. The carboxyl group is subsequently transferred by carboxybiotin to a second active site in the CT domain, where pyruvate is carboxylated to generate oxaloacetate. The BCCP domain transfers the tethered cofactor between the two remote active sites. The allosteric binding site in PC offers a target for modifiers of activity that may be useful in the treatment of obesity or type II diabetes, and the mechanistic insights gained from the complete structural description of RePC (R. etli) permit detailed investigations into the individual catalytic and regulatory sites of the enzyme.
The reaction mechanism can be subdivided into two partial reactions (see figure to the right). In the first reaction, ATP is carboxylated to produce carbonic phosphoric anhydride [–O(–O)P(=O)O–C(=O)O–] which in turn carboxylates a biotin cofactor that is covalently attached to a lysine residue of the BCCP domain. Carbonic phosphoric anhydride decomposes into carbon dioxide and phosphate prior to attack by the enzyme linked biotin molecule. In most species, this reaction requires acetyl-CoA as an allosteric activator binding to the PT domain. In the second reaction, occurring in the CT domain of an adjacent monomer, carbon dioxide is transferred to the acceptor molecule, pyruvate, to form oxaloacetate. The reaction proceeds via the removal of a proton from pyruvate, by an as yet unidentified active site residue, to generate an enolate intermediate. The enolate intermediate then attacks CO2 transiently released from the enzyme linked biotin molecule. The resultant oxaloacetate is released. The biotin molecule is protonated by the aforementioned active site residue and released from the active site of the CT domain to be recarboxylated. The major regulator of enzyme activity, acetyl-CoA, stimulates the cleavage of ATP in the first partial reaction and also it has been shown to induce a conformational change in the tetrameric structure of the enzyme.
Role in gluconeogenesis
During gluconeogenesis, pyruvate carboxylase is involved in the synthesis of phosphoenolpyruvate (PEP) from pyruvate. Pyruvate is first converted by pyruvate carboxylase to oxaloacetate (OAA) in the mitochondrion requiring hydrolysis of one molecule of ATP. The OAA is then decarboxylated and simultaneously phosphorylated, which is catalyzed by one of two isoforms of phosphoenolpyruvate carboxykinase (PEPCK) either in the cytosol or in the mitochondria to produce PEP. Under ordinary gluconeogenic conditions, OAA is converted into PEP by mitochondrial PEPCK; the resultant PEP is then transported out of the mitochondrial matrix by an anion transporter carrier system, and converted into glucose by cytosolic gluconeogenic enzymes. However, during starvation when cytosolic NADH concentration is low and mitochrondrial NADH levels are high oxaloacetate can be used as a shuttle of reducing equivalents. As such OAA is converted into malate by mitochondrial Malate dehydrogenase (MDH). After export into the cytosol, malate is converted back into OAA, with concomitant reduction of NAD+; OAA is subsequently converted to PEP which is available for gluconeogenesis in the cytosol along with the transported reducing equivalent NADH.
Very high levels of PC activity, together with high activities of other gluconeogenic enzymes including PEPCK, fructose-1,6-bisphosphatase and glucose-6-phosphatase in liver and kidney cortex, suggest that a primary role of PC is to participate in gluconeogenesis in these organs. During fasting or starvation when endogenous glucose is required for certain tissues (brain, white blood cells and kidney medulla), expression of PC and other gluconeogenic enzymes is elevated. In rats and mice, alteration of nutrition status has been shown to affect hepatic PC activity. Fasting promotes hepatic glucose production sustained by an increased pyruvate flux, and increases in PC activity and protein concentration; diabetes similarly increases gluconeogenesis through enhanced uptake of substrate and increased flux through liver PC in mice and rats. Similarly to other gluconeogenic enzymes, PC is positively regulated by glucagon and glucocorticoids while negatively regulated by insulin. Further supporting the key role of PC in gluconeogenesis, in dairy cattle, which have hexose absorption ability at adequate nutrition levels, PC and the associated gluconeogenic enzyme PEPCK are markedly elevated during the transition to lactation in proposed support of lactose synthesis for milk production.
Aside from the role of PC in gluconeogenesis, PC serves an anaplerotic role (an enzyme catalyzed reaction that can replenish the supply of intermediates in the citric acid cycle) for the tricarboxylic acid cycle (essential to provide oxaloacetate), when intermediates are removed for different biosynthetic purposes.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
As a crossroad between carbohydrate and lipid metabolism, pyruvate carboxylase expression in gluconeogenic tissues, adipose tissues and pancreatic islets must be coordinated. In conditions of over nutrition, PC levels are increased in pancreatic β-cells to increase pyruvate cycling in response to chronically elevated levels of glucose. In contrast, PC enzyme levels in the liver are decreased by insulin; during periods of overnutrition adipocyte tissue is expanded with extreme expression of PC and other lipogenic enzymes. Hepatic control of glucose levels is still regulated in an over nutrition situation, but in obesity induced type 2 diabetes the regulation of peripheral glucose levels is no longer under regulation of insulin. In type 2 diabetic rats, chronic exposure of β-cells to glucose due to peripheral insulin resistance results in decreased PC enzyme activity and decreased pyruvate cycling The continued overproduction of glucose by hepatocytes causes dramatic alteration of β-cell gene expression with large increases in normally suppressed genes, and equivalent decreases in expression of mRNA for insulin, ion pumps necessary for insulin secretion, and metabolic enzymes related to insulin secretion, including pyruvate carboxylase Concurrently adipose tissue develops insulin resistance causing accumulation of triaglycerols and non-esterified fatty acids in circulation; these not only further impairing β-cell function, but also further decreasing PC expression. These changes result in the decline of the β-cell phenotype in decompensated diabetes.
A deficiency of pyruvate carboxylase can cause lactic acidosis as a result of lactate build up. Normally, excess pyruvate is shunted into gluconeogenesis via conversion of pyruvate into oxaloacetate, but because of the enzyme deficiency, excess pyruvate is converted into lactate instead. As a key role of gluconeogenesis is in the maintenance of blood sugar, deficiency of pyruvate carboxylase can also lead to hypoglycemia.
- PDB 2QF7; Jitrapakdee S, St Maurice M, Rayment I, Cleland WW, Wallace JC, Attwood PV (August 2008). "Structure, mechanism and regulation of pyruvate carboxylase". Biochem. J. 413 (3): 369–87. doi:10.1042/BJ20080709. PMC 2859305. PMID 18613815.
- Utter MF, Keech DB (May 1960). "Formation of oxaloacetate from pyruvate and carbon dioxide". J. Biol. Chem. 235: PC17–8. PMID 13840551.
- Cohen ND, Beegen H, Utter MF, Wrigley NG (March 1979). "A re-examination of the electron microscopic appearance of pyruvate carboxylase from chicken liver". J. Biol. Chem. 254 (5): 1740–7. PMID 762171.
- Jitrapakdee S, Vidal-Puig A, Wallace JC (April 2006). "Anaplerotic roles of pyruvate carboxylase in mammalian tissues". Cell. Mol. Life Sci. 63 (7-8): 843–54. doi:10.1007/s00018-005-5410-y. PMID 16505973.
- Jitrapakdee S, Nezic MG, Cassady AI, Khew-Goodall Y, Wallace JC (July 2002). "Molecular cloning and domain structure of chicken pyruvate carboxylase". Biochem. Biophys. Res. Commun. 295 (2): 387–93. doi:10.1016/S0006-291X(02)00651-4. PMID 12150961.
- Jitrapakdee S, Walker ME, Wallace JC (June 1996). "Identification of novel alternatively spliced pyruvate carboxylase mRNAs with divergent 5'-untranslated regions which are expressed in a tissue-specific manner". Biochem. Biophys. Res. Commun. 223 (3): 695–700. doi:10.1006/bbrc.1996.0958. PMID 8687459.
- Kondo S, Nakajima Y, Sugio S, Yong-Biao J, Sueda S, Kondo H (March 2004). "Structure of the biotin carboxylase subunit of pyruvate carboxylase from Aquifex aeolicus at 2.2 A resolution". Acta Crystallogr. D Biol. Crystallogr. 60 (Pt 3): 486–92. doi:10.1107/S0907444904000423. PMID 14993673.
- Yu LP, Xiang S, Lasso G, Gil D, Valle M, Tong L (June 2009). "A symmetrical tetramer for S. aureus pyruvate carboxylase in complex with coenzyme A". Structure 17 (6): 823–32. doi:10.1016/j.str.2009.04.008. PMC 2731552. PMID 19523900.
- St Maurice M, Reinhardt L, Surinya KH, Attwood PV, Wallace JC, Cleland WW, Rayment I (August 2007). "Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme". Science 317 (5841): 1076–9. doi:10.1126/science.1144504. PMID 17717183.
- Stark R, Pasquel F, Turcu A, et al. (2009). "Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion.". Journal of Biological Chemistry 284 (39): 26578–26590. doi:10.1074/jbc.M109.011775. PMC 2785346. PMID 19635791.
- Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI (October 1991). "Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR". Science 254 (5031): 573–6. doi:10.1126/science.1948033. PMID 1948033.
- Bizeau ME, Short C, Thresher JS, Commerford SR, Willis WT, Pagliassotti MJ (2001). "Increased pyruvate flux capacities account for diet induced increase in gluconeogenesis ‘’in vitro’’". Am. J. Physiol. Regul. Integr. Comp. Physiol. 281 (2): R427–R433. PMID 11448844.
- Salto R, Sola M, Olicer F J, Vargas A M (Dec 1996). "Effects of starvation, diabetes, and carbon tetrachloride intoxication on rat kidney cortex and liver pyruvate carboxylase levels". Arch. Physiol. Biochem. 104 (7): 845–850. doi:10.1076/apab.104.7.845.13111. PMID 9127680.
- Large V, Beylot M (June 1999). "Modifications of citric acid cycle activity and gluconeogenesis in strepozotocin induced diabetes and effects of metformin". Diabetes 48 (6): 1251–1257. doi:10.2337/diabetes.48.6.1251. PMID 10342812.
- Greenfield RB, Cecava MJ, Donkin SS (2002). "Changes in mRNA expression for gluconeogenic enzymes in the liver of dairy cattle during transition to lactation". Journal of Dairy Science 82 (6): 1228–1236. doi:10.3168/jds.S0022-0302(00)74989-7. PMID 10877388.
- Liu YQ, Han J, Epstein PN, Long YS (Dec 2005). "Enhanced rat β-cell proliferation in 60% pancreatectomized islets by increased glucose metabolic flux through pyruvate carboxylase pathway". Am. J. Physiol. Endocrinol. Metab 288 (3): E471–E478. doi:10.1152/ajpendo.00427.2004. PMID 15507531.
- Desvergne B, Michalik L, Wahli W (April 2006). "Transcriptional regulation of metabolism". Physiol. Rev 86 (2): 465–514. doi:10.1152/physrev.00025.2005. PMID 16601267.
- Lynch CJ, McCall KM, Billingsley ML, Bohlen LM, Hreniuk SP, Martin LF, Witters LA, Vannucci SJ (May 1992). "Pyruvate carboxylase in genetic obesity". Am. J. Physiol 262 (5 Pt 1): E608–E618. PMID 1375435.
- MacDonald MJ, Tang J, Polonsky KS (Nov 1996). "Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats". Diabetes 45 (11): 1626–1630. doi:10.2337/diabetes.45.11.1626. PMID 8866570.
- McDonald MJ, Efendic S, Ostenson CG (July 1996). "Normalization by insulin of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat". Diabetes 45 (7): 886–890. doi:10.2337/diabetes.45.7.886. PMID 8666138.
- Laybutt DR, Glandt M, Xu G, Ahn YB, Trivedi N, Bonner-Weir S, Weir GC (Jan 2003). "Critical reduction in β-cell mass results in two distinct outcomes over time. Adaption with impaired glucose tolerance or decompensated diabetes". J. Biol. Chem. 278 (5): 2997–3005. doi:10.1074/jbc.M210581200. PMID 12438314.
- Poitout V, Robertson R P (Feb 2002). "Secondary ß-cell failure in type 2 diabetes-a convergence of glucotoxicity and lipotoxicity". Endocrinology 143 (2): 339–342. doi:10.1210/en.143.2.339. PMID 11796484.
- Boucher A, Lu D, Burgess SC, Telamaque-Potts S, Jensen M V, Mulder H, Wang M Y, Unger R H, Sherry A D, Newgard C B (2004). "Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue". J. Biol. Chem. 279 (26): 27263–27271. doi:10.1074/jbc.M401167200. PMID 15073188.
- Busch AK, Cordery D, Denyer GS, Biden TJ (Apr 2002). "Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic exposure on pancreatic β-cell function". Diabetes 51 (4): 977–987. doi:10.2337/diabetes.51.4.977. PMID 11916915.
- Iizuka K, Nakajima H, Namba M, Miyagawa J, Mijazaki J, Hanafusa T, Matsuzawa Y (Jan 2002). "Metabolic consequences of long-term exposure of pancreatic β-cells to free fatty acid with special reference to glucose insensitivity". Biochim. Biophys. Acta 1586 (1): 23–31. doi:10.1016/s0925-4439(01)00082-5. PMID 11781146.
- García-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, Saudubray JM (January 2006). "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects". Ann. Neurol. 59 (1): 121–7. doi:10.1002/ana.20709. PMID 16278852.
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.
HMGL-like Provide feedback
This family contains a diverse set of enzymes. These include various aldolases and a region of pyruvate carboxylase.
Internal database links
|Similarity to PfamA using HHSearch:||AP_endonuc_2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000891
Pyruvate carboxylase (EC) (PC), a member of the biotin-dependent enzyme family, is involved in the gluconeogenesis by mediating the carboxylation of pyruvate to oxaloacetate. Biotin-dependent carboxylase enzymes perform a two step reaction. Enzyme-bound biotin is first carboxylated by bicarbonate and ATP and the carboxyl group temporarily bound to biotin is subsequently transferred to an acceptor substrate such as pyruvate [PUBMED:11851389]. PC has three functional domains: a biotin carboxylase (BC) domain, a carboxyltransferase (CT) domain which perform the second part of the reaction and a biotinyl domain [PUBMED:7780827, PUBMED:10229653]. The mechanism by which the carboxyl group is transferred from the carboxybiotin to the pyruvate is not well understood.
The pyruvate carboxyltransferase domain is also found in other pyruvate binding enzymes and acetyl-CoA dependent enzymes suggesting that this domain can be associated with different enzymatic activities.
This domain is found towards the N-terminal region of various aldolase enzymes. This N-terminal TIM barrel domain [PUBMED:12764229] interacts with the C-terminal domain. The C-terminal DmpG_comm domain (INTERPRO) is thought to promote heterodimerisation with members of INTERPRO to form a bifunctional aldolase-dehydrogenase [PUBMED:12764229].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||catalytic activity (GO:0003824)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This large superfamily of TIM barrel enzymes all contain a common phosphate binding site. The phosphate is found in a variety of cofactors and ligands such as FMN [1,2].
The clan contains the following 57 members:Ala_racemase_N ALAD Aldolase AP_endonuc_2 BtpA CdhD CutC DAHP_synth_1 DAHP_synth_2 DeoC DHDPS DHO_dh DHquinase_I DUF1341 DUF2090 DUF556 DUF561 DUF692 DUF993 Dus F_bP_aldolase FMN_dh G3P_antiterm Glu_syn_central Glu_synthase His_biosynth HMGL-like IGPS IMPDH iPGM_N MtrH NanE NAPRTase NeuB NMO OMPdecase Orn_Arg_deC_N Oxidored_FMN PcrB PdxJ PhosphMutase PRAI Pterin_bind QRPTase_C Racemase_4 RhaA Ribul_P_3_epim SOR_SNZ Tagatose_6_P_K ThiG TIM TIM-br_sig_trns TMP-TENI Transaldolase Trp_syntA UvdE UxuA
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
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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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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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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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|Seed source:||Pfam-B_71 (release 2.1)|
|Number in seed:||20|
|Number in full:||12580|
|Average length of the domain:||236.80 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||43.97 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
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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.
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 7 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 HMGL-like domain has been found. There are 111 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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