Summary: CUB-like domain
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CUB domain Edit Wikipedia article
CUB domain is an evolutionarily conserved protein domain.
The CUB domain (for complement C1r/C1s, Uegf, Bmp1) is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated. These proteins are involved in a diverse range of functions, including complement activation, developmental patterning, tissue repair, axon guidance and angiogenesis, cell signalling, fertilisation, haemostasis, inflammation, neurotransmission, receptor-mediated endocytosis, and tumour suppression. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin).
Proteins containing a CUB domain include:
- Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.
- Cricetidae sp. (Hamster) serine protease Casp, which degrades type I and IV collagen and fibronectin in the presence of calcium.
- Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.
- Vertebrate enteropeptidase (EC 184.108.40.206), a type II membrane protein of the intestinal brush border, which activates trypsinogen.
- Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.
- Sea urchin blastula proteins BP10 and SpAN.
- C. elegans hypothetical proteins F42A10.8 and R151.5.
- Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.
- Fibropellins I and III from Strongylocentrotus purpuratus (Purple sea urchin).
- Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.
- Mammalian spermadhesins.
- Xenopus laevis embryonic protein UVS.2, which is expressed during dorsoanterior development.
Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains.
Spermadhesin is a subdivision of the CUB domain family and forms a major component of the mammalian seminal fluid. Spermadhesins are 110-133 amino acid polypeptides. The binding activity of spermadhesins, e.g. heparin and carbohydrate binding, enables their central role in promoting attachment of the spermatozoa to carbohydrate groups on the glycoproteins found on the surface of oocytes. The spermadhesins from pigs, bulls and stallions show 40-98% similarity in their amino acid sequences and all possess a disulphide bond between adjacent cysteine residues. The porcine spermadhesin polypeptides are coded by five closely linked genes. Bovine spermadhesin relies on a significantly lower number of genes with only two being associated with expression of this protein in bovine seminal fluid. Redundant genetic coding for spermadhesins have been observed in chimpanzees, dogs, and humans. The region correlating to spermadhesin genes in rat and mice DNA is void of any spermadhesin code. These variations in expression and genetic coding of spermadhesins are seen to result from evolutionary adjustments in genes as a consequence of mutations and deletions in genetic material.
Some CUB domains appear to be involved in oligomerisation and/or recognition of substrates and binding partners. For example, in the complement proteases, the CUB domains mediate dimerisation and binding to collagen-like regions of target proteins (e.g. C1q for C1r/C1s). The structure of CUB domains consists of a beta-sandwich with a jelly-roll fold. Almost all CUB domains contain four conserved cysteines that probably form two disulphide bridges (C1-C2, C3-C4). The CUB1 domains of C1s and Map19 have calcium-binding sites.
Human genes encoding proteins containing this domain include:
- ATRN, ATRNL1, BMP1,
- C1R, C1RL, C1S, CDCP2, CSMD1, CSMD2, CSMD3, CUBN, CUZD1,
- DCBLD1, DCBLD2, DMBT1, DREG,
- KREMEN1, KREMEN2,
- LRP10, LRP12, LRP3,
- MASP1, MASP2, MFRP,
- NETO1, NETO2, NRP1, NRP2,
- OVCH1, OVCH2,
- PCOLCE, PCOLCE2, PDGFC, PDGFD, PRSS7,
- SCUBE1, SCUBE2, SCUBE3, SEZ6, SEZ6L, SEZ6L2, ST14,
- TLL1, TLL2, TMPRSS7, TNFAIP6
- Bork P, Beckmann G (May 1993). "The CUB domain. A widespread module in developmentally regulated proteins". Journal of Molecular Biology 231 (2): 539–45. doi:10.1006/jmbi.1993.1305. PMID 8510165.
- Bork P (Apr 1991). "Complement components C1r/C1s, bone morphogenic protein 1 and Xenopus laevis developmentally regulated protein UVS.2 share common repeats". FEBS Letters 282 (1): 9–12. doi:10.1016/0014-5793(91)80433-4. PMID 2026272.
- Perry SE, Robinson P, Melcher A, Quirke P, Bühring HJ, Cook GP, Blair GE (Mar 2007). "Expression of the CUB domain containing protein 1 (CDCP1) gene in colorectal tumour cells". FEBS Letters 581 (6): 1137–42. doi:10.1016/j.febslet.2007.02.025. PMID 17335815.
- Romero A, Varela PF, Sanz L, Töpfer-Petersen E, Calvete JJ (Mar 1996). "Crystallization and preliminary X-ray diffraction analysis of boar seminal plasma spermadhesin PSP-I/PSP-II, a heterodimer of two CUB domains". FEBS Letters 382 (1-2): 15–7. doi:10.1016/0014-5793(96)00133-0. PMID 8612739.
- Töpfer-Petersen E, Romero A, Varela PF, Ekhlasi-Hundrieser M, Dostàlovà Z, Sanz L, Calvete JJ (1998). "Spermadhesins: a new protein family. Facts, hypotheses and perspectives". Andrologia 30 (4-5): 217–24. doi:10.1111/j.1439-0272.1998.tb01163.x. PMID 9739418.
- Haase B, Schlötterer C, Hundrieser ME, Kuiper H, Distl O, Töpfer-Petersen E, Leeb T., Evolution of the spermadhesin gene family, Gene. (2005) 352, P-20-29
- Blanc G, Font B, Eichenberger D, Moreau C, Ricard-Blum S, Hulmes DJ, Moali C (Jun 2007). "Insights into how CUB domains can exert specific functions while sharing a common fold: conserved and specific features of the CUB1 domain contribute to the molecular basis of procollagen C-proteinase enhancer-1 activity". The Journal of Biological Chemistry 282 (23): 16924–33. doi:10.1074/jbc.M701610200. PMID 17446170.
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.
CUB-like domain Provide feedback
This is a family of hypothetical C. elegans proteins. The aligned region has no known function nor do any of the proteins which possess it. However, this domain is related to the CUB domain.
Internal database links
|Similarity to PfamA using HHSearch:||CUB|
This tab holds annotation information from the InterPro database.
InterPro entry IPR003366This domain is found in a family of hypothetical Caenorhabditis elegans proteins. The aligned region has no known function nor do any of the proteins which possess it. However, this domain is related to the CUB domain (INTERPRO). The aligned region is approximately 130 amino acids long and contains two conserved cysteine residues.
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.
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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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, 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 UniProtKB sequence database using the family HMM
- 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.
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.
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_1716 (release 5.4)|
|Author:||Bashton M, Bateman A|
|Number in seed:||24|
|Number in full:||269|
|Average length of the domain:||113.70 aa|
|Average identity of full alignment:||20 %|
|Average coverage of the sequence by the domain:||26.11 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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a FASTA-format file
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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....
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.