Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
70  structures 1003  species 0  interactions 8587  sequences 167  architectures

Family: Disintegrin (PF00200)

Summary: Disintegrin

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 "Disintegrin". More...

Disintegrin Edit Wikipedia article

Disintegrin
Desintegrin heterodimer.png
Structure of disintegrin heterodimer from Echis carinatus
Identifiers
SymbolDisintegrin
PfamPF00200
InterProIPR001762
PROSITEPDOC00351
SCOPe1kst / SUPFAM
OPM superfamily227
OPM protein2ao7
Membranome538

Disintegrins are a family of small proteins (45–84 amino acids in length) from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion.[1][2]

Operation

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.[3] The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant.[4]

Types of disintegrin

Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin,[5] schistatin,[6] echistatin,[7] elegantin, eristicophin, flavoridin,[8] halysin, kistrin, mojastin (Crotalus scutulatus), rubistatin (Crotalus ruber), tergeminin, salmosin,[9] tzabcanin (Crotalus simus tzabcan)[10] and triflavin.

Disintegrins are split into 5 classes: small, medium, large, dimeric, and snake venom metalloproteinases.[11]

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.[12]

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[13] 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.[14] 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).[15] 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.

See also

References

  1. ^ McLane MA, Sanchez EE, Wong A, Paquette-Straub C, Perez JC (2004). "Disintegrins". Curr Drug Targets Cardiovasc Haematol Disord. 4 (4): 327–55. doi:10.2174/1568006043335880. PMID 15578957.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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): 57–66. doi:10.1042/BJ20041343. PMC 1134932. PMID 15535803.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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
  11. ^ Calvete, J (2005). "Structure-function correlations of snake venom disintegrins". Curr Pharm Des. 11 (7): 825–835. doi:10.2174/1381612053381783.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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 (3): 671–675. doi:10.1042/bj2860671. PMC 1132955. PMID 1417724.

External links

This article incorporates text from the public domain Pfam and InterPro: IPR001762

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Disintegrin Provide feedback

No Pfam abstract.

Internal database links

External database links

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.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Alignments

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 and the UniProtKB sequence database. More...

View options

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.

  Seed
(523)
Full
(8587)
Representative proteomes UniProt
(15700)
RP15
(958)
RP35
(2627)
RP55
(6919)
RP75
(9797)
Jalview View  View  View  View  View  View  View 
HTML View             
PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(523)
Full
(8587)
Representative proteomes UniProt
(15700)
RP15
(958)
RP35
(2627)
RP55
(6919)
RP75
(9797)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

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.

  Seed
(523)
Full
(8587)
Representative proteomes UniProt
(15700)
RP15
(958)
RP35
(2627)
RP55
(6919)
RP75
(9797)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

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...

Trees

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.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: disintegrin;
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD
Number in seed: 523
Number in full: 8587
Average length of the domain: 74.80 aa
Average identity of full alignment: 45 %
Average coverage of the sequence by the domain: 9.60 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 35.1 35.1
Trusted cut-off 35.1 35.1
Noise cut-off 35.0 35.0
Model length: 76
Family (HMM) version: 25
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Hide

Weight segments by...


Change the size of the sunburst

Small
Large

Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

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.

Structures

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 70 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

Loading structure mapping...

AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JX23 View 3D Structure Click here
A0A0G2K0E8 View 3D Structure Click here
A0A0G2K693 View 3D Structure Click here
A0A0R4IDF3 View 3D Structure Click here
A0A0R4INJ8 View 3D Structure Click here
A0A1D5NT24 View 3D Structure Click here
A0A1W2Q6C2 View 3D Structure Click here
A0A2R8Q0T5 View 3D Structure Click here
A0A2R8Q3V6 View 3D Structure Click here
A0A2R8Q748 View 3D Structure Click here
A2RSG8 View 3D Structure Click here
B2RSY5 View 3D Structure Click here
B2RUD9 View 3D Structure Click here
D3ZB52 View 3D Structure Click here
D3ZEP8 View 3D Structure Click here
D3ZIP6 View 3D Structure Click here
D3ZPM7 View 3D Structure Click here
D3ZT36 View 3D Structure Click here
E7F494 View 3D Structure Click here
E7F698 View 3D Structure Click here
E7F6J8 View 3D Structure Click here
E7FGJ0 View 3D Structure Click here
E9PTA4 View 3D Structure Click here
E9PTQ3 View 3D Structure Click here
F1LW54 View 3D Structure Click here
F1LWE4 View 3D Structure Click here
F1LXB5 View 3D Structure Click here
F1M8J6 View 3D Structure Click here
F1M9Z9 View 3D Structure Click here
F1Q4N9 View 3D Structure Click here
F1Q5U0 View 3D Structure Click here
F1QDC4 View 3D Structure Click here
F1QF43 View 3D Structure Click here
F1QFD2 View 3D Structure Click here
F1QU24 View 3D Structure Click here
F8VQ03 View 3D Structure Click here
F8W3T1 View 3D Structure Click here
G3V9N4 View 3D Structure Click here
G5EDW5 View 3D Structure Click here
G5EFD5 View 3D Structure Click here
G5EFD9 View 3D Structure Click here
M0R5P8 View 3D Structure Click here
O13766 View 3D Structure Click here
O14672 View 3D Structure Click here
O35227 View 3D Structure Click here
O35598 View 3D Structure Click here
O35674 View 3D Structure Click here
O43184 View 3D Structure Click here
O43506 View 3D Structure Click here
O75077 View 3D Structure Click here
O75078 View 3D Structure Click here
O88839 View 3D Structure Click here
P70505 View 3D Structure Click here
P78325 View 3D Structure Click here
P78536 View 3D Structure Click here
P97776 View 3D Structure Click here
Q05910 View 3D Structure Click here
Q10743 View 3D Structure Click here
Q13443 View 3D Structure Click here
Q13444 View 3D Structure Click here
Q3B7V9 View 3D Structure Click here
Q3TTE0 View 3D Structure Click here
Q5BK84 View 3D Structure Click here
Q60718 View 3D Structure Click here
Q60813 View 3D Structure Click here
Q61072 View 3D Structure Click here
Q61824 View 3D Structure Click here
Q63180 View 3D Structure Click here
Q63202 View 3D Structure Click here
Q6IMH6 View 3D Structure Click here
Q6IMH7 View 3D Structure Click here
Q6QU65 View 3D Structure Click here
Q7M762 View 3D Structure Click here
Q7M763 View 3D Structure Click here
Q7M766 View 3D Structure Click here
Q7ZYZ9 View 3D Structure Click here
Q811Q3 View 3D Structure Click here
Q811Q4 View 3D Structure Click here
Q8CGQ2 View 3D Structure Click here
Q8K410 View 3D Structure Click here
Q8R534 View 3D Structure Click here
Q8TC27 View 3D Structure Click here
Q923W9 View 3D Structure Click here
Q94316 View 3D Structure Click here
Q99965 View 3D Structure Click here
Q9BZ11 View 3D Structure Click here
Q9H013 View 3D Structure Click here
Q9H2U9 View 3D Structure Click here
Q9JI76 View 3D Structure Click here
Q9JLN6 View 3D Structure Click here
Q9P0K1 View 3D Structure Click here
Q9QYV0 View 3D Structure Click here
Q9R157 View 3D Structure Click here
Q9R158 View 3D Structure Click here
Q9R159 View 3D Structure Click here
Q9R160 View 3D Structure Click here
Q9R1V4 View 3D Structure Click here
Q9R1V6 View 3D Structure Click here
Q9R1V7 View 3D Structure Click here
Q9UKF2 View 3D Structure Click here
Q9UKF5 View 3D Structure Click here
Q9UKJ8 View 3D Structure Click here
Q9UKQ2 View 3D Structure Click here
Q9VAC5 View 3D Structure Click here
Q9VAI2 View 3D Structure Click here
Q9VJW9 View 3D Structure Click here
Q9Y3Q7 View 3D Structure Click here
Q9Z0F8 View 3D Structure Click here
Q9Z1K9 View 3D Structure Click here
U3JAD1 View 3D Structure Click here
X2JE21 View 3D Structure Click here