Molecular mechanisms involved in platelet binding to collagen.

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Molecular mechanisms involved in platelet binding to collagen.

Platelets are small anuclear cells found in blood. They are only 2-3 µm in diameter and their average lifespan is 8-12 days. Platelets circulate the body in the blood stream and they are important in blood clotting (haemostasis). Haemostasis is important to the human body, Platelets along with fibrin form a blood clot to stop bleeding. Lack of platelets in the blood could cause excess bleeding, this also means a high platelet count could cause excess blood clotting which could result in a stroke or even a heart attack. It could also cause the blood vessels that lead to different parts of the body to get blocked. When injury occurs the endothelium layer in the blood vessel is damaged and the sub endothelium is exposed to blood. The platelets are then exposed to von Willebrand Factor, collagen, tissue factors and other proteins. Collagen is a protein made up of three polypeptide strands and acts as a ligand. Collagen adheres with the platelets causing them to aggregate forming a clot (MarilynW. Verkleij and Michael J. Barnes 1998). This report focuses on the molecular mechanisms involved in platelet binding to collagen.

On the platelet surface there are different collagen binding proteins. Von Willebrand Factor (vWF) is found in the blood plasma and binds to collagen and platelets in the blood. It is produced by the endothelial cells and also by megakaryocytes. The initial interactions between collagen in the sub endothelium and platelets is by collagen bound vWF binding to proteins on the platelet surface called Glycoprotein Ib (GPIb) (1268.pdf) However the GPIb-vWF complex is not strong enough for permanent adhesion and the platelets roll on the collagen surface. This is most likely due to the shear stress in the blood vessel as this limits the interaction time between the ligand-receptor pair. vWF binds by its A1 domain to GPIb and via its A3 domain mediating collagen binding to the sub endothelium. (2684.pdf)

Firm adhesion between collagen and platelets occurs using two distinct receptors, the immune receptor homolog glycoprotein VI (GPVI) and the integrin α2β1 (alpha2 beta1). Integrins have a generally conserved structure and are αβ heterodimers. They have an extracellular globular head, which comprises with the N terminal regions of both the alpha and beta chains. They are connected by a rigid and long stalk to a c-terminal cytoplasmic tail and a pair of membrane spanning helices. When the cytoplasmic tails undertake binding events this allosterically controls the adhesiveness of the extracellular domains. This is known as inside out signalling. The ligand binding site of the integrin is called the metal ion-dependent adhesion site or MIDAS motif, these along with the exposed side chains surrounding them are required for ligand binding. The alpha2 beta 1 integrin is a receptor for laminin and collagen, it can also be found on several different cell types. The fibrillar collagens which are exposed when injury occurs are bound by the integrin which is supported with magnesium or manganese. It binds like a complete receptor in a cation-dependant manner. Binding occurs via the alpha2 subunit I domain to a collagen motif with the sequence Gly-Phe-Hyp-Gly-Glu-Arg. Integrin α2β1 exhibits specific binding to fibrillar collagens. (inside out signalling.pdf)

Glycoprotein VI (GPVI) also plays a big role in collagen interactions. It belongs to the immunoglobulin superfamily and is a collagen receptor. It has a small cytoplasmic tail made up of -51 amino acids, a transmembrane domain, mucin like core and two extracellular immunoglobulin like domains. GPVI also binds collagen - related peptide and snake venom protein, convulxin. Studies have shown that the main ligand recognising molecule in GPVI is the surface of the N-terminal immunoglobulin domain which is centred on Lys59. These studies involved mutagenesis of the recombinant ectodomain of GPVI. GPVI specifically binds to fibrous collagen and not soluble collagen. The high affinity binding site for collagen on GPVI is made up of two chains of GPVI. This is due to the dimeric form of GPVI being the only form that has a high affinity to collagen. The dimeric form of GPIV is therefore one that is found on platelets. (gpvi.pdf) GPVI co-associates with Fcr y-chain in the collagen receptor complex, this then causes the association of Syk.

In conclusion the molecular mechanisms involved in platelets binding to collagen involve von Willebrand Factors binding to glycoprotein Ib which is found on the platelet, integrin α2β1 receptor binding to collagen and glycoprotein GPVI binding to collagen. These mechanisms then cause the platelets to adhere to each other and to the sub endothelium which results in a blood clot.

MarilynW. Verkleij, L. F. M., C. Graham Knight, Philip G. de Groot, and a. J. J. S. Michael J. Barnes (1998). "Simple Collagen-Like Peptides Support Platelet Adhesion Under Static But Not

Under Flow Conditions: Interaction Via a2b1 and von Willebrand Factor With

Specific Sequences in Native Collagen Is a Requirement to Resist Shear Forces." Blood 91(No 10): 3808-3816.

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