Platelet physiology and thrombosis.
Glycoprotein (GP) Ibalpha of the GPIb-IX-V complex and GPVI bind von Willebrand factor (vWF) and collagen, respectively, and are critical for the initial interaction of circulating platelets with the injured vessel wall under high shear conditions. These interactions act together to facilitate stable thrombus formation in vivo. Ligand binding to GPIb-IX-V of the leucine-rich repeat family or GPVI of the immunoglobulin superfamily initiates platelet activation, and inside-out activation of the platelet integrin, alphaIIbbeta3, that binds vWF or fibrinogen and mediates platelet aggregation. The binding site for GPIbalpha on vWF resides in the conserved A1 domain, encompassing the disulfide bond at Cys509-Cys695. This domain may be activated to bind platelet GPIbalpha under shear stress by anchoring of the downstream A3 domain to collagen and conformational distortion of the intervening A2 domain. The N-terminal, 282 residues, of GPIbalpha contains the binding site for vWF-A1, as well as the conserved A-type domain of the leukocyte integrin alphaMbeta2 (alphaM I domain) and P-selectin expressed on activated platelets or endothelial cells. Endothelial P-selectin also supports surface expression of vWF multimers, enabling platelet vessel wall interaction by at least two mechanisms. Recent evidence suggests GPVI that binds collagen, and GPIb-IX-V that binds collagen-bound vWF are physically associated on the platelet surface. This review will focus on the structure-function of primary platelet adhesion receptors, GPIb-IX-V and GPVI, and how they act together to regulate platelet thrombus formation in pathophysiology.
Andrews
Robert K
RK
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia. rob.andrews@med.monash.edu.au
Berndt
Michael C
MC
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D001665:Binding Sites; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000737:chemistry; D008666:Metalloendopeptidases / Q000378:metabolism; D008954:Models, Biological; D019007:P-Selectin / Q000737:chemistry; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013927:Thrombosis / Q000097:blood*; D014841:von Willebrand Factor / Q000378:metabolism
D004220:Disulfides; D008024:Ligands; D016177:Macrophage-1 Antigen; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D005340:Fibrinogen; D003094:Collagen; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D007930:Leucine