Disintegrins are a family of small

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s (45–84

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s in length) from

viper venoms The Viperidae (vipers) are a family of snakes found in most parts of the world, except for Antarctica, Australia, Hawaii, Madagascar, and various other isolated islands. They are venomous and have long (relative to non-vipers), hinged fangs t ...

that function as potent inhibitors of both

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

aggregation and

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

-dependent

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

Operation

Disintegrins work by countering the

blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

steps, inhibiting the clumping of

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

. They interact with the beta-1 and -3 families of

integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

receptors. Integrins are

cell receptor In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recept ...

s involved in cell–cell and cell–

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

interactions, serving as the final common pathway leading to aggregation via formation of platelet–platelet bridges, which are essential in

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...

and

haemostasis In biology, hemostasis American and British English spelling differences#ae and oe, or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is Bleeding, hemorrhage). ...

. 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 Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clo ...

to the receptor–glycoprotein complex of activated platelets. Disintegrins act as

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...

s, inhibiting aggregation induced by ADP,

thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...

, platelet-activating factor and

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

. The role of disintegrin in preventing blood

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

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 A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be c ...

, 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 Colubroidea is a superfamily of snakes in the clade Colubroides that includes Colubridae, with some studies splitting Colubridae into multiple families that make up Colubroidea. Historically, Colubroidea also included other caenophidian snakes su ...

, 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 Trimerelysin I (, ''Trimeresurus metalloendopeptidase I'', ''hemorrhagic proteinase HR1A'', ''hemorrhagic metalloproteinase HR1A'', ''metalloproteinase HR1A'') is an enzyme. This enzyme catalyses the following chemical reaction : Cleavage of only ...

(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 Adam; el, Ἀδάμ, Adám; la, Adam is the name given in Genesis 1-5 to the first human. Beyond its use as the name of the first man, ''adam'' is also used in the Bible as a pronoun, individually as "a human" and in a collective sense as " ...

and

ADAMTS ADAMTS (short for a disintegrin and metalloproteinase with thrombospondin motifs) is a family of multidomain extracellular protease enzymes. 19 members of this family have been identified in humans, the first of which, ADAMTS1, was described in 19 ...

protein families, which include important protease enzymes. ** The secreted protease

ADAMTS13 ADAMTS13 (''a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13'')—also known as ''von Willebrand factor-cleaving protease'' (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor ( ...

, found in serum, cleaves

Von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopen ...

and acts as a natural, endogenous inhibitor of platelet adhesion and aggregation. **

ADAM2 Disintegrin and metalloproteinase domain-containing protein 2 or Beta-fertilin is an enzyme that in humans is encoded by the ''ADAM2'' gene. Function This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Me ...

(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 Disintegrin and metalloproteinase domain-containing protein 7 is a protein that in humans is encoded by the ADAM7 gene. ADAM7 is an 85-kDa enzyme that is a member of the transmembrane ADAM (A Disintegrin and Metalloprotease) protein family. Mem ...

(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.

References

External links