Disintegrin
Encyclopedia
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
.
They work by countering the blood clotting steps, inhibiting the clumping of platelets. They interact with the beta-1 and -3 families of integrins receptors. Integrin 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 antagonist
s, 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.
Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin, schistatin, echistatin, elegantin, eristicophin, flavoridin, halysin, kistrin, tergeminin, salmosin 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:
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation and integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
-dependent cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
.
They work by countering the blood clotting steps, inhibiting the clumping of platelets. They interact with the beta-1 and -3 families of integrins receptors. Integrin are cell receptors involved in cell–cell and cell–extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
interactions, serving as the final common pathway leading to aggregation via formation of platelet–platelet bridges, which are essential in thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
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
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
to the receptor–glycoprotein complex of activated platelets. Disintegrins act as receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s, inhibiting aggregation induced by ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, platelet-activating factor
Platelet-activating factor
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis...
and collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
. The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant.
Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin, schistatin, echistatin, elegantin, eristicophin, flavoridin, halysin, kistrin, tergeminin, salmosin 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 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. 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). 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.
- ADAMADAM ProteinADAM is a family of peptidase proteins. It is also known as the adamalysin family or MDC family. ADAMs are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, activating it...
and ADAMTSADAMTSADAMTS is a family of peptidases. 19 members of this family have been identified in humans. Known functions of the ADAMTS proteases include processing of procollagens and von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan...
protein families, which include important protease enzymes. As an example, the secreted protease ADAMTS13ADAMTS13ADAMTS13 —also known as von Willebrand factor-cleaving protease —is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor , a large protein involved in blood clotting...
, found in serum, cleaves Von Willebrand factorVon Willebrand factorvon Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
and acts as a natural, endogenous, inhibitor of platelet adhesion and aggregation.