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Disintegrin Edit Wikipedia article
Structure of disintegrin heterodimer from Echis carinatus
Disintegrins work by countering the blood clotting steps, inhibiting the clumping of platelets. They interact with the beta-1 and -3 families of integrins receptors. Integrins are cell receptors involved in cell–cell and cell–extracellular matrix interactions, serving as the final common pathway leading to aggregation via formation of platelet–platelet bridges, which are essential in thrombosis and haemostasis. Disintegrins contain an RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp) sequence motif that binds specifically to integrin IIb-IIIa receptors on the platelet surface, thereby blocking the binding of fibrinogen to the receptor–glycoprotein complex of activated platelets. Disintegrins act as receptor antagonists, inhibiting aggregation induced by ADP, thrombin, platelet-activating factor and collagen. The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant.
Types of disintegrin
Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin, schistatin, echistatin, elegantin, eristicophin, flavoridin, halysin, kistrin, mojastin (Crotalus scutulatus), rubistatin (Crotalus ruber), tergeminin, salmosin, tzabcanin (Crotalus simus tzabcan) and triflavin.
Disintegrins are split into 5 classes: small, medium, large, dimeric, and snake venom metalloproteinases.
Small Disintegrins: 49-51 amino acids, 4 disulfide bonds
Medium Disintegrins: 70 amino acids, 6 disulfide bonds
Large Disintegrins: 84 amino acids, 7 disulfide bonds
Dimeric Disintegrins: 67 amino acids, 4 intra-chain disulfide bonds
Snake Venom Metalloproteinases: 100 amino acids, 8 disulfide bond
Evolution of disintegrin family
Disintegrins evolved via gene duplication of an ancestral protein family, the ADAM family. Small, medium, large, and dimeric disintegrin family are found only in the family Viperidae, suggesting duplication and diversification about 12-20 million years ago. Snake venom metalloproteinases are found through the entire superfamily Colubroidea, suggesting that they evolved before Colubroidea diversified roughly 60 million years ago.
Other sources of disintegrin proteins
Disintegrin-like proteins are found in various species ranging from slime mold to humans. Some other proteins known to contain a disintegrin domain are:
- Some snake venom zinc metalloproteinases consist of an N-terminal catalytic domain fused to a disintegrin domain. Such is the case for trimerelysin I (HR1B), atrolysin-e (Ht-e) and trigramin. It has been suggested that these proteinases are able to cleave themselves from the disintegrin domains and that the latter may arise from such a post-translational processing.
- The beta-subunit of guinea pig sperm surface protein PH30. PH30 is a protein involved in sperm-egg fusion. The beta subunit contains a disintegrin at the N-terminal extremity.
- Mammalian epididymial apical protein 1 (EAP I). EAP I is associated with the sperm membrane and may play a role in sperm maturation. Structurally, EAP I consists of an N-terminal domain, followed by a zinc metalloproteinase domain, a disintegrin domain, and a large C-terminal domain that contains a transmembrane region.
- ADAM and ADAMTS protein families, which include important protease enzymes. As an example, the secreted protease ADAMTS13, found in serum, cleaves Von Willebrand factor and acts as a natural, endogenous inhibitor of platelet adhesion and aggregation.
- McLane MA, Sanchez EE, Wong A, Paquette-Straub C, Perez JC (2004). "Disintegrins". Curr Drug Targets Cardiovasc Haematol Disord. 4 (4): 327–55. PMID 15578957.
- Lu X, Lu D, Scully MF, Kakkar VV (2005). "Snake venom metalloproteinase containing a disintegrin-like domain, its structure-activity relationships at interacting with integrins". Curr Med Chem Cardiovasc Hematol Agents. 3 (3): 249–60. doi:10.2174/1568016054368205. PMID 15974889.
- Rahman S, Xu CS (2001). "Identification by Site-directed Mutagenesis of Amino Acid Residues Flanking RGD Motifs of Snake Venom Disintegrins for Their Structure and Function". Acta Biochim. Biophys. Sin. 33 (2): 153–157. PMID 12050803.
- Lu X, Lu D, Scully MF, Kakkar VV (2006). "Integrins in drug targeting-RGD templates in toxins". Curr Pharm Des. 12 (22): 2749–69. doi:10.2174/138161206777947713. PMID 16918409.
- Calvete JJ, Monleon D, Celda B, Paz Moreno-Murciano M, Marcinkiewicz C (2003). "NMR solution structure of the non-RGD disintegrin obtustatin". J. Mol. Biol. 329 (1): 135–45. doi:10.1016/S0022-2836(03)00371-1. PMID 12742023.
- Betzel C, Sharma S, Singh TP, Perbandt M, Yadav S, Kaur P, Bilgrami S (2005). "Crystal structure of the disintegrin heterodimer from saw-scaled viper (Echis carinatus) at 1.9 A resolution". Biochemistry. 44 (33): 11058–66. doi:10.1021/bi050849y. PMID 16101289.
- Calvete JJ, Kovacs H, Monleon D, Celda B, Esteve V (2005). "Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR". Biochem J. 387 (Pt 1): 57. doi:10.1042/BJ20041343. PMC . PMID 15535803.
- Mizuno H, Morita T, Fujii Y, Fujimoto Z, Horii K, Okuda D (2003). "Crystal structure of trimestatin, a disintegrin containing a cell adhesion recognition motif RGD". J. Mol. Biol. 332 (5): 1115–22. doi:10.1016/S0022-2836(03)00991-4. PMID 14499613.
- Lee W, Shin J, Kang I, Hong SY, Chung K, Jang Y, Kim DS (2003). "Solution structure of a novel disintegrin, salmosin, from Agkistrondon halys venom". Biochemistry. 42 (49): 14408–15. doi:10.1021/bi0300276. PMID 14661951.
- Saviola, A.J., Modahl, C.M. and Mackessy, S.P., 2015. Disintegrins of Crotalus simus tzabcan venom: Isolation, characterization and evaluation of the cytotoxic and anti-adhesion activities of tzabcanin, a new RGD disintegrin. Biochimie, 116, pp.92-102. https://doi.org/10.1016/j.biochi.2015.07.005
- Calvete, J (2005). "Structure-function correlations of snake venom disintegrins". Curr Pharm Design. 11 (7): 825–835. doi:10.2174/1381612053381783.
- Juárez P, Comas I, González-Candelas F, Calvete JJ (2008). "Evolution of Snake Venom Disintegrins by Positive Darwinian Selection". Molecular Biology and Evolution. 25 (11): 2391–2407. doi:10.1093/molbev/msn179. PMID 18701431.
- Teixeira Cde F, Fernandes CM, Zuliani JP, Zamuner SF (2005). "Inflammatory effects of snake venom metalloproteinases". Mem. Inst. Oswaldo Cruz. 100: 181–4. doi:10.1590/s0074-02762005000900031. PMID 15962120.
- Turck CW, Myles DG, Primakoff P, Blobel CP, Wolfsberg TG, White JM (1992). "A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion". Nature. 356 (6366): 248–252. doi:10.1038/356248a0. PMID 1552944.
- Hall L, Jones R, Barker PJ, Perry AC (1992). "A mammalian epididymal protein with remarkable sequence similarity to snake venom haemorrhagic peptides". Biochem. J. 286: 671–675. PMC . PMID 1417724.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR001762
Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion [PUBMED:15578957, PUBMED:15974889]. Integrin receptors are involved in cell-cell and cell-extracellular matrix interactions, serving as the final common pathway leading to aggregation via formation of platelet-platelet bridges, which are essential in thrombosis and haemostasis. Disintegrins contain an RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp) sequence motif that binds specifically to integrin IIb-IIIa receptors on the platelet surface, thereby blocking the binding of fibrinogen to the receptor-glycoprotein complex of activated platelets. Disintegrins act as receptor antagonists, inhibiting aggregation induced by ADP, thrombin, platelet-activating factor and collagen [PUBMED:12050803]. The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant [PUBMED:16918409].
Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin [PUBMED:12742023], schistatin [PUBMED:16101289], echistatin [PUBMED:15535803], elegantin, eristicophin, flavoridin [PUBMED:14499613], halysin, kistrin, tergeminin, salmosin [PUBMED:14661951] and triflavin.
Disintegrin-like proteins are found in various species ranging from slime mold to humans. Some other proteins known to contain a disintegrin domain are:
- Some snake venom zinc metalloproteinases [PUBMED:15962120] consist of an N-terminal catalytic domain fused to a disintegrin domain. Such is the case for trimerelysin I (HR1B), atrolysin-e (Ht-e) and trigramin. It has been suggested that these proteinases are able to cleave themselves from the disintegrin domains and that the latter may arise from such a post-translational processing.
- The beta-subunit of guinea pig sperm surface protein PH30 [PUBMED:1552944]. PH30 is a protein involved in sperm-egg fusion. The beta subunit contains a disintegrin at the N-terminal extremity.
- Mammalian epididymial apical protein 1 (EAP I) [PUBMED:1417724]. EAP I is associated with the sperm membrane and may play a role in sperm maturation. Structurally, EAP I consists of an N-terminal domain, followed by a zinc metalloproteinase domain, a disintegrin domain, and a large C-terminal domain that contains a transmembrane region.
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:
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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...
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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.
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.
|Number in seed:||601|
|Number in full:||4258|
|Average length of the domain:||75.40 aa|
|Average identity of full alignment:||44 %|
|Average coverage of the sequence by the domain:||9.54 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|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....
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:
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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 3 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 Disintegrin domain has been found. There are 68 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.
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