Disintegrin

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.{{cite journal |vauthors=Rahman S, Xu CS |title=Identification by Site-directed Mutagenesis of Amino Acid Residues Flanking RGD Motifs of Snake Venom Disintegrins for Their Structure and Function |journal=Acta Biochim. Biophys. Sin. |volume=33 |issue=2 |pages= 153–157|year=2001 |pmid=12050803}} The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant.{{cite journal |vauthors=Lu X, Lu D, Scully MF, Kakkar VV |title=Integrins in drug targeting-RGD templates in toxins |journal=Curr Pharm Des |volume=12 |issue=22 |pages= 2749–69|year=2006 |pmid=16918409 |doi=10.2174/138161206777947713}}

Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin,{{cite journal |vauthors=Calvete JJ, Monleon D, Celda B, Paz Moreno-Murciano M, Marcinkiewicz C |title=NMR solution structure of the non-RGD disintegrin obtustatin |journal=J. Mol. Biol. |volume=329 |issue=1 |pages= 135–45|year=2003 |pmid=12742023 |doi=10.1016/S0022-2836(03)00371-1}} schistatin,{{cite journal |vauthors=Betzel C, Sharma S, Singh TP, Perbandt M, Yadav S, Kaur P, Bilgrami S |title=Crystal structure of the disintegrin heterodimer from saw-scaled viper (Echis carinatus) at 1.9 A resolution |journal=Biochemistry |volume=44 |issue=33 |pages= 11058–66|year=2005 |pmid=16101289 |doi=10.1021/bi050849y}} echistatin,{{cite journal |vauthors=Calvete JJ, Kovacs H, Monleon D, Celda B, Esteve V |title=Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR |journal=Biochem J |volume=387 |issue= Pt 1|pages= 57–66|year=2005 |pmid=15535803 |pmc=1134932 |doi=10.1042/BJ20041343}} elegantin, eristicophin, flavoridin,{{cite journal |vauthors=Mizuno H, Morita T, Fujii Y, Fujimoto Z, Horii K, Okuda D |title=Crystal structure of trimestatin, a disintegrin containing a cell adhesion recognition motif RGD |journal=J. Mol. Biol. |volume=332 |issue=5 |pages= 1115–22|year=2003 |pmid=14499613 |doi=10.1016/S0022-2836(03)00991-4}} halysin, kistrin, mojastin (Crotalus scutulatus), rubistatin (Crotalus ruber), tergeminin, salmosin,{{cite journal |vauthors=Lee W, Shin J, Kang I, Hong SY, Chung K, Jang Y, Kim DS |title=Solution structure of a novel disintegrin, salmosin, from Agkistrondon halys venom |journal=Biochemistry |volume=42 |issue=49 |pages= 14408–15|year=2003 |pmid=14661951 |doi=10.1021/bi0300276}} tzabcanin (Crotalus simus tzabcan)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 and triflavin.

Disintegrins are split into 5 classes: small, medium, large, dimeric, and snake venom metalloproteinases.{{cite journal|last=Calvete|first=J|title=Structure-function correlations of snake venom disintegrins|journal=Curr Pharm Des|year=2005|volume=11|issue=7|pages=825–835|doi=10.2174/1381612053381783|pmid=15777237}}

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

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.{{cite journal|vauthors=Juárez P, Comas I, González-Candelas F, Calvete JJ |title=Evolution of Snake Venom Disintegrins by Positive Darwinian Selection|journal=Molecular Biology and Evolution|year=2008|volume=25|issue=11|pages=2391–2407|doi=10.1093/molbev/msn179|pmid=18701431|doi-access=free}}

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{{cite journal |vauthors=Teixeira Cde F, Fernandes CM, Zuliani JP, Zamuner SF |title=Inflammatory effects of snake venom metalloproteinases |journal=Mem. Inst. Oswaldo Cruz |volume=100 |pages= 181–4|year=2005 |pmid=15962120 |doi=10.1590/s0074-02762005000900031|doi-access=free |hdl=1807/8219 |hdl-access=free }} 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).{{cite journal |doi=10.1038/356248a0 |vauthors=Turck CW, Myles DG, Primakoff P, Blobel CP, Wolfsberg TG, White JM |title=A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion |journal=Nature |volume=356 |issue=6366 |pages=248–252 |year=1992 |pmid=1552944|bibcode=1992Natur.356..248B |s2cid=4233338 }} 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).{{cite journal |vauthors=Hall L, Jones R, Barker PJ, Perry AC |title=A mammalian epididymal protein with remarkable sequence similarity to snake venom haemorrhagic peptides |journal=Biochem. J. |volume=286 |issue= 3|pages=671–675 |year=1992 |pmid=1417724 |pmc=1132955|doi=10.1042/bj2860671 }} 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.

• ADAM Protein
• Evolution of snake venom

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• {{MeshName|Disintegrins}}

{{InterPro content|IPR001762}}

Category:Animal proteins

Category:Venomous snakes