Summary: Cation-independent mannose-6-phosphate receptor repeat
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Mannose 6-phosphate receptor". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Mannose 6-phosphate receptor Edit Wikipedia article
|Cation-independent mannose-6-phosphate receptor repeat|
|Cation-dependent mannose-6-phosphate receptor|
|Locus||Chr. 12 p13|
|Cation-independent mannose-6 phosphate receptor|
|Locus||Chr. 6 q25q27|
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR), while the smaller receptor (CD-MPR) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
Both of these receptors bind terminal mannose 6-phosphate with similar affinity (CI-MPR = 7 μM, CD-MPR = 8 μM) and have similar signals in their cytoplasmic domains for intracellular trafficking.
Elizabeth Neufeld was studying patients who had multiple inclusion bodies present in their cells. Due to the large amount of inclusion bodies she named this condition I-cell disease. These inclusion bodies represented lysosomes that were filled with undigestable material. At first Neufeld thought these patients must have a lack of lysosomal enzymes. . Further study showed that all of the lysosomal enzymes were being made but they were being incorrectly targeted. Instead of being sent to the lysosome, they were being secreted. Furthermore these mis-targeted enzymes were found to not be phosphorylated. Therefore Neufeld suggested that I-cell disease was caused by a deficiency in the enzymes that add a specific mannose 6-phosphate tag onto lysosomal enzymes so they can be targeted to the lysosome.
Studies of I-cell disease led to the discovery of the receptors that bind to this specific tag. Firstly the CI-MPR was discovered and isolated through the use of affinity chromatography. However scientists discovered that some of the lysosomal enzymes still reached the lysosome in the absence of the CI-MPR. This led to the identification of another mannose 6-phosphate binding receptor, the CD-MPR, which binds its ligand in the presence of a divalent cation such as Mn2+.
The genes for each receptor have been cloned and characterised. It is thought that they have evolved from the same ancestral gene as there is conservation in some of their intron/ exon borders and there is a homology in their binding domains.
Mechanism of targeting
Lysosomal enzymes are synthesised in the rough endoplasmic reticulum along with a range of other secretory proteins. A specific recognition tag has evolved to prevent these harmful lysosomal enzymes from being secreted and to ensure they are targeted to the lysosome. This tag is a mannose 6-phosphate residue.
Once the lysosomal enzyme has been translocated into the rough endoplasmic reticulum an oligosaccharide composed of Glc3 Man9 GlcNAc2 is transferred en bloc to the protein. The oligosaccharide present on lysosomal enzymes is processed in the same manner as other secretory proteins whilst it is translocated from the endoplasmic reticulum to the cis-Golgi.
In the cis-Golgi a GlcNAc phosphotransferase (EC 184.108.40.206) adds a GlcNAc-1-phosphate residue onto the 6-hydroxyl group of a specific mannose residue within the oligosaccharide. This forms a phosphodiester: Man-phosphate-GlcNAc. Once the phosphodiester has been formed the lysosomal enzyme will be translocated through the Golgi apparatus to the trans-Golgi. In the trans-Golgi a phosphodiesterase (EC 220.127.116.11) will remove the GlcNAc residue exposing the mannose 6-phosphate tag, allowing the lysosomal enzymes to bind to the CI-MPR and the CD-MPR. The MPR-lysosomal enzyme complex is translocated to a pre-lysosomal compartment, known as an endosome, in a clathrin-coated vesicle. This targeting away from the secretory pathway is achieved by the presence of a specific sorting signal, an acidic cluster/dileucine motif, in the cytoplasmic tails of the MPRs. Both MPRs bind their ligands most effectively at pH 6 – 7; thus enabling the receptors to bind to the lysosomal enzymes in the trans-Golgi and release them in the acidified environment of the endosome. Once the enzyme has dissociated from the mannose 6-phosphate receptor, it is translocated from the endosome to the lysosome where the phosphate tag is removed from the enzyme.
MPRs are not found in the lysosomes; they cycle mainly between the trans-Golgi network and endosomes. The CI-MPR is also present on the cell surface. Around 10-20% of the CI-MPR can be found at the cell membrane. Its function here is to capture any mannose 6-phosphate tagged enzymes that have accidentally entered the secretory pathway. Once it binds to a lysosomal enzyme the receptor becomes internalised rapidly. Internalisation is mediated by a sorting signal in its cytoplasmic tail – a YSKV motif. This ensures that all harmful lysosomal enzymes will be targeted to the lysosome.
Knockout mice studies
Mice lacking the CI-MPR die at day 15 of gestation due to cardiac hyperplasia. The mice suffer from abnormal growth because they are unable to regulate the levels of free IGF-II (insulin-like growth factor type II). Death of the mice can be prevented if the IGF-II allele is also knocked out. Further analysis of the embryos also showed that they display defects in the targeting of lysosomal enzymes as they have an increased level of phosphorylated lysosomal enzymes in their amniotic fluid. Approximately 70% of lysosomal enzymes are secreted in the absence of the CI-MPR – this suggests that the CD-MPR is unable to compensate for its loss.
When the CD-MPR is knocked out in mice we observe mice that appear healthy apart from the fact that they have defects in the targeting of multiple lysosomal enzymes. These mice display elevated levels of phosphorylated lysosomal enzymes in their blood and they accumulate undigested material in their lysosomes.
From these knockout mice we can deduce that both receptors are needed for the efficient targeting of lysosomal enzymes. If we compare the lysosomal enzymes that are secreted by the two different knockout cell lines we see different sets of enzymes. This suggests that each MPR interacts preferentially with a subset of lysosomal enzymes.
The CI-MPR and CD-MPR are structurally distinct receptors however they share an overall general structure as they are both type I integral membrane proteins. Both receptors have a large N-terminal extracytoplasmic domain, one transmembrane domain and a short C-terminal cytoplasmic tail. These cytoplasmic tails contain multiple sorting signals; some of which can be either phosphorylated or palmitoylated.
CI-MPR: The CI-MPR is ~300 kDa. The N-terminal extracytoplasmic domain contains 15 contiguous P-type carbohydrate recognition domains. They are referred to as MRH (mannose 6-phosphate receptor homology) domains. The domains are homologous because they have:
- A similar size - each one has around 150 amino acid residues
- Conserved amino acid residues – between 14-38% sequence identity 
- Conserved positioning of 6 specific Cysteine residues that are involved in forming disulphide bonds 
The structure of 7 out of the 15 domains has been determined, using X-ray crystallography, and they seem to share a similar fold. The CI-MPR exists mainly as a dimer in the membrane. Domains 3, 5 and 9 have been found to bind to mannose 6-phosphate. Domains 3 and 9 can bind to mannose 6-phosphate with high affinity. Domain 5 only binds Man-6-phosphate with a weak affinity. However domain 5 has also been shown to bind to the phosphodiester, Man-phosphate-GlcNAc. This is a safety mechanism for the cell – it means it is able to bind to lysosomal enzymes that have escaped the action of the enzyme that removes the GlcNAc residue. Combining these 3 domains allows the CI-MPR to bind to a wide range of phosphorylated glycan structures. Domain 11 binds to IGF-II.
CD-MPR: The CD-MPR is much smaller than the CI-MPR – it is only ~46 kDa. Its N-terminal extracytoplasmic domain contains only 1 P-type carbohydrate recognition domain. The CD-MPR exists mainly as a dimer in the membrane. However monomeric and tetrameric forms are also thought to exist as well. The equilibrium between these different oligomers is affected by pH, temperature and presence of mannose 6-phosphate residues. Each monomer forms a 9 stranded ß-barrel which can bind to a single mannose 6-phosphate residue.
Mannose 6-phosphate Binding
The CI-MPR and CD-MPR bind mannose 6-phosphate in a similar fashion. Both form a set of hydrogen bonds between key residues and characteristic hydroxyl groups on the mannose residue. Hydrogen bonds to hydroxyl groups at positions 2, 3 and 4 make the site specific for mannose alone.
Both MPRs share 4 residues that are essential for ligand binding. Mutation of any of these residues results in the loss of mannose 6-phosphate binding. These residues are glutamine, arginine, glutamic acid and tyrosine and are responsible for forming the hydrogen bonds that contact specific hydroxyl groups in the mannose residue.
- Type – hybrid or high mannose structures
- Presence of the phosphomonoester (mannose 6-phosphate) or phosphodiester (Man-phosphate-GlcNAc)
- Number of mannose 6-phosphate tags
- Location of the mannose 6-phosphate tag
The CI-MPR and CD-MPR are able to bind to this wide range of N-glycan structures by having a different binding site architecture. The MPRs also bind to the phosphate group in a slightly different manner. Domain 3 of the CI-MPR uses Ser-386 and an ordered water molecule to bind to the phosphate moiety. On the other hand the CD-MPR uses residues Asp-103, Asn-104 and His-105 to form favourable hydrogen bonds to the phosphate group. The CD-MPR also contains a divalent cation Mn2+ which forms favourable hydrogen bonds with the phosphate moiety.
CI-MPR and Cancer
It is well-established that the CI-MPR binds mannose 6-phosphate but there is a growing body of evidence that suggests the CI-MPR also binds to unglycosylated IGF-II. It is thought that when the CI-MPR is present on the cell surface, domain 11 will bind to any IGF-II free in the extracellular matrix. The receptor is then rapidly internalised, along with IGF-II, through a YSKV motif present in the CI-MPR’s cytoplasmic tail. IGF-II will then be targeted to the lysosome where it will be degraded. This regulates the level of free IGF-II in the body.
This function of the CI-MPR was determined through the use of knockout mice. It was observed that CI-MPR deficient mice had an increased level of free IGF-II and enlarged organs (around a 30% increase in size ). These mice die at day 15 of gestation due to cardiac hyperplasia. Death of the mice could be prevented when the IGF-II allele was also knocked out. When the CI-MPR and the IGF-II allele are knocked out we see a normal mouse as there is no longer a growth factor present that needs to be regulated.
Due to CI-MPR’s ability to modulate the levels of IGF-II it has been suggested it may play a role as a tumour suppressor. Studies of multiple human cancers have shown that a loss of the CI-MPR function is associated with a progression in tumourigenesis. Loss of heterozygosity (LOH) at the CI-MPR locus has been displayed in multiple cancer types including liver and breast. However this is a relatively new concept and many more studies will have to investigate the relationship between the CI-MPR and cancer.
- Drickamer K, Taylor ME (2011). Introduction to glycobiology (3 ed.). Oxford [u.a.]: Oxford University Press. pp. 177–181. ISBN 0199569118.
- Hoflack B, Kornfeld S (July 1985). "Lysosomal enzyme binding to mouse P388D1 macrophage membranes lacking the 215-kDa mannose 6-phosphate receptor: evidence for the existence of a second mannose 6-phosphate receptor". Proc. Natl. Acad. Sci. U.S.A. 82 (13): 4428–32. doi:10.1073/pnas.82.13.4428. PMC 391114. PMID 3160044.
- Hoflack B, Kornfeld S (October 1985). "Purification and characterization of a cation-dependent mannose 6-phosphate receptor from murine P388D1 macrophages and bovine liver". J. Biol. Chem. 260 (22): 12008–14. PMID 2931431.
- Junghans U, Waheed A, von Figura K (September 1988). "The 'cation-dependent' mannose 6-phosphate receptor binds ligands in the absence of divalent cations". FEBS Lett. 237 (1–2): 81–4. doi:10.1016/0014-5793(88)80176-5. PMID 2971570.
- Tong PY, Kornfeld S (May 1989). "Ligand interactions of the cation-dependent mannose 6-phosphate receptor. Comparison with the cation-independent mannose 6-phosphate receptor". J. Biol. Chem. 264 (14): 7970–5. PMID 2542255.
- Johnson KF, Chan W, Kornfeld S (December 1990). "Cation-dependent mannose 6-phosphate receptor contains two internalization signals in its cytoplasmic domain". Proc. Natl. Acad. Sci. U.S.A. 87 (24): 10010–4. doi:10.1073/pnas.87.24.10010. PMC 55304. PMID 2175900.
- Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler M (2009). "P-type Lectins". Essentials of glycobiology (2nd ed.). Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press. ISBN 0879697709.
- Hoflack, B., Komfeld, S. (1985). "Lysosomal enzyme binding to mouse P388D1 macrophage membranes lacking the 215 kDa mannose 6-phosphate receptor: evidence for the existence of a second mannose 6-phosphate receptor". Proc. Natl. Acad. Sci. 82: 4428–32. doi:10.1073/pnas.82.13.4428. PMC 391114. PMID 3160044.
- Hoflack B, Kornfeld S (1985). "Purification and characterisation of a cation-dependent mannose 6-phosphate receptor from murine P388D1 macrophages and bovine liver". J. Biol. Chem. 260 (22): 12008–14. PMID 2931431.
- Reitman ML, Kornfeld S (1981). "Lysosomal enzymes targeting. N-Acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes". J. Biol. Chem. 256 (23): 11977–80. PMID 6457829.
- Duncan JR, Kornfeld S (March 1988). "Intracellular movement of two mannose 6-phosphate receptors: return to the Golgi apparatus". J. Cell Biol. 106 (3): 617–28. doi:10.1083/jcb.106.3.617. PMC 2115106. PMID 2964450.
- Le Borgne R, Hoflack B (1997). "Mannose 6-phosphate receptors regulate the formation of clathrin-coated vesicles in the TGN". J. Cell Biol. 137 (2): 335–45. doi:10.1083/jcb.137.2.335. PMC 2139777. PMID 9128246.
- Ghosh P, Dahms NM, Kornfeld S (2003). "Mannose 6-phosphate receptors: New twists in the tale.". Nature Reviews Molecular Cell Biology 4 (3): 202–212. doi:10.1038/nrm1050. PMID 12612639.
- Pohlmann, R., Nagel, G., Hille, A., Wendland, M., Waheed, A., Braulke, T. & von Figura, K. (1989). "Mannose 6-phosphate specific receptors: structure and function". Biochem Soc Trans 17: 15.
- Johnson KF, Chan W, Kornfeld S (1990). "Cation-dependent mannose 6-phosphate receptor contains two internalisation signal in its cytoplasmic domain". Proc. Natl. Acad. Sci. 87: 10010–4. doi:10.1073/pnas.87.24.10010. PMC 55304. PMID 2175900.
- Bohnsack RN, Song X, Olson LJ, Kudo M, Gotschall RR, Canfield WM, Cummings RD, Smith DF, Dahms NM (2009). "Cation-independent Mannose 6-phosphate Receptor A Composite of Distinct Phosphomannosyl Binding Sites". Journal of Biological Chemistry 284 (50): 35215–35226. doi:10.1074/jbc.M109.056184. PMC 2787381. PMID 19840944.
- Tong PY, Kornfeld S (1989). "Ligand interactions of the cation-dependent mannose 6-phosphate receptor. Comparison with the cation-independent mannose 6-phosphate receptor". J. Biol. Chem. 264 (14): 7970–5. PMID 2542255.
- De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL (1996). "M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity". Nat. Genet. 11 (4): 447–9. doi:10.1038/ng1295-447. PMID 7493029.
- De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL (1995). "Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors". Oncogene 10 (9): 1725–9. PMID 7753549.
- Duncan JR, Kornfeld S (1988). "Intracellular movement of two mannose 6-phosphate receptors: return to the Golgi apparatus". J. Cell. Biol. 106: 617–28. doi:10.1083/jcb.106.3.617. PMC 2115106. PMID 2964450.
- Junghans U, Waheed A, von Figura K (1988). "The 'cation-dependent' mannose 6-phosphate receptor binds ligands in the absence of divalent cations". FEBS Left 237 (1-2): 81–4. doi:10.1016/0014-5793(88)80176-5. PMID 2971570.
- Hawkes C, Kar S (2004). "The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system". Brain Res. Brain Res. Rev. 44 (2–3): 117–40. doi:10.1016/j.brainresrev.2003.11.002. PMID 15003389.
- Killian JK, Jirtle RL (1999). "Genomic structure of the human M6P/IGF2 receptor". Mamm. Genome 10 (1): 74–7. doi:10.1007/s003359900947. PMID 9892739.
- Ishiwata T, Bergmann U, Kornmann M, Lopez M, Beger HG, Korc M (1997). "Altered expression of insulin-like growth factor II receptor in human pancreatic cancer". Pancreas 15 (4): 367–73. doi:10.1097/00006676-199711000-00006. PMID 9361090.
- Imperial College Lectins Research Information
- UniProtKB/ Swiss-Prot entry for the human cation-independent mannose 6-phosphate receptor
- UniProtKB/ Swiss-Prot entry for the human cation-dependent mannose 6-phosphate receptor
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.
Cation-independent mannose-6-phosphate receptor repeat Provide feedback
The cation-independent mannose-6-phosphate receptor contains 15 copies of a repeat.
Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ; , Nature 1987;329:301-307.: Insulin-like growth factor II receptor as a multifunctional binding protein. PUBMED:2957598 EPMC:2957598
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000479The cation-independent mannose-6-phosphate receptor is a type I membrane protein responsible for transport of phosphorylated lysosomal enzymes from the golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds insulin growth factor. It contains 15 copies of a repeat.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||integral to membrane (GO:0016021)|
|Molecular function||transporter activity (GO:0005215)|
|Biological process||transport (GO:0006810)|
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:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
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.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_764 (release 3.0)|
|Number in seed:||12|
|Number in full:||1464|
|Average length of the domain:||136.00 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||77.56 %|
|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:||13|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
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....
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:
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 is 1 interaction 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 CIMR domain has been found. There are 57 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.
Loading structure mapping...