Disintegrin
| Disintegrin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of disintegrin heterodimer from Echis carinatus | |||||||||
| Identifiers | |||||||||
| Symbol | Disintegrin | ||||||||
| Pfam | PF00200 | ||||||||
| InterPro | IPR001762 | ||||||||
| PROSITE | PDOC00351 | ||||||||
| SCOP | 1kst | ||||||||
| SUPERFAMILY | 1kst | ||||||||
| OPM superfamily | 256 | ||||||||
| OPM protein | 2ao7 | ||||||||
| |||||||||
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] and triflavin.
Disintegrins are split into 5 classes: small, medium, large, dimeric, and snake venom metalloproteinases.[10]
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 Viperidae family, suggesting duplication and diversification about 12-20 million years ago. Snake venom metalloproteinases are found through the entire Colubroidea superfamily, suggesting that they evolved before Colubroidea diversified roughly 60 million years ago.[11]
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[12] 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.[13] 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).[14] 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
- ↑ McLane MA, Sanchez EE, Wong A, Paquette-Straub C, Perez JC (2004). "Disintegrins". Curr Drug Targets Cardiovasc Haematol Disord 4 (4): –. 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): –. 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): –. PMID 12050803.
- ↑ Lu X, Lu D, Scully MF, Kakkar VV (2006). "Integrins in drug targeting-RGD templates in toxins". Curr Pharm Des 12 (22): –. 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): –. 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): –. 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): –. doi:10.1042/BJ20041343. PMC 1134932. 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): –. 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): –. doi:10.1021/bi0300276. PMID 14661951.
- ↑ 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: –. 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 1132955. PMID 1417724.
External links
- Disintegrins at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the public domain Pfam and InterPro IPR001762