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Disintegrin

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Proteins from viper venom inhibiting platelets aggregation
Disintegrin
Structure of disintegrin heterodimer from Echis carinatus
Identifiers
SymbolDisintegrin
PfamPF00200
InterProIPR001762
PROSITEPDOC00351
SCOP21kst / SCOPe / SUPFAM
OPM superfamily227
OPM protein2ao7
Membranome538
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.

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. 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.
  • ADAM and ADAMTS protein families, which include important protease enzymes.
    • The secreted protease ADAMTS13, found in serum, cleaves Von Willebrand factor and acts as a natural, endogenous inhibitor of platelet adhesion and aggregation.
    • ADAM2 (beta-fertilin, 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.
    • ADAM7 (Mammalian epididymial apical protein 1, EAP I). ADAM7 is associated with the sperm membrane and may play a role in sperm maturation. Structurally, ADAM7 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.

See also

References

  1. Oliveira, Ana L.; Viegas, Matilde F.; da Silva, Saulo L.; Soares, Andreimar M.; Ramos, Maria J.; Fernandes, Pedro A. (July 2022). "The chemistry of snake venom and its medicinal potential". Nature Reviews Chemistry. 6 (7): 451–469. doi:10.1038/s41570-022-00393-7. ISSN 2397-3358. PMC 9185726.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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
  12. Calvete, J (2005). "Structure-function correlations of snake venom disintegrins". Curr Pharm Des. 11 (7): 825–835. doi:10.2174/1381612053381783. PMID 15777237.
  13. 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.
  14. 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. hdl:1807/8219. PMID 15962120.
  15. 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. Bibcode:1992Natur.356..248B. doi:10.1038/356248a0. PMID 1552944. S2CID 4233338.
  16. 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 Categories: