Snake venom modulators of platelet adhesion receptors and their ligands.
In thrombosis, platelet aggregation is initiated by a specific membrane glycoprotein (GP) Ib-IX-V complex binding to its adhesive ligand, von Willebrand factor, in the matrix of ruptured atherosclerotic plaques or in plasma exposed to high hydrodynamic shear stress. This process closely resembles normal haemostasis at high shear, where GP Ib-IX-V-dependent platelet adhesion to von Willebrand factor in the injured blood vessel wall initiates platelet activation and integrin alphaIIb beta3 (GP IIb-IIIa)-dependent platelet aggregation. At low shear, other receptors such as those that bind collagen, the integrin alpha2beta1 (GP Ia-IIa) or GP VI, mediate platelet adhesion. Recently, snake venom proteins have been identified that selectively modulate platelet function, either promoting or inhibiting platelet aggregation by targeting GP Ib-IX-V, alpha2beta1, GP VI, alphaIIb beta3, or their respective ligands. Interestingly, these venom proteins typically belong to one of two major protein families, the C-type lectin family or the metalloproteinase-disintegrins. This review focuses on recent insights into structure-activity relationships of snake venom proteins that regulate platelet function, and the ways in which these novel probes have contributed in unexpected ways to our understanding of the molecular mechanisms underlying thrombosis.
Andrews
R K
RK
Hazel and Pip Appel Vascular Biology Laboratory, Baker Medical Research Institute, Melbourne, Australia. rkandrews@hotmail.com
Berndt
M C
MC
D000595:Amino Acid Sequence; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology; D016024:Receptors, Cytoadhesin / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism; D012910:Snake Venoms / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000378:metabolism
D018955:CD36 Antigens; D008024:Ligands; D016024:Receptors, Cytoadhesin; D018179:Receptors, Thrombin; D012910:Snake Venoms; D014841:von Willebrand Factor