Structure-activity relationships of snake toxins targeting platelet receptors, glycoprotein Ib-IX-V and glycoprotein VI.
Initiation of thrombus formation involves the platelet adhesion receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor (vWF) and collagen, respectively. These interactions trigger intracellular signals leading to degranulation, elevation of cytosolic Ca2+, cytoskeletal rearrangements, and "inside-out" activation of the integrin, GPIIb-IIIa (alphaIIbbeta3) that binds von Willebrand Factor (vWF) or fibrinogen and mediates platelet aggregation. GPIbalpha (the vWF-binding subunit of GPIb-IX-V) of the leucine-rich repeat protein family and GPVI of the immunoglobulin superfamily not only have a parallel physiological function, but recent studies of these receptors have revealed structure-activity relationships amongst snake venom toxins which target them. Two families of venom proteins, the C-type lectin-like proteins and metalloproteinase-disintegrins, target GPIbalpha, GPVI and/or the collagen-binding integrin, GPIa-IIa (alpha2beta1). Members of the C-type lectin family interact specifically with GPIbalpha (echicetin, alboaggregin-B, agglucetin), GPVI (convulxin, ophioluxin) or GPIa-IIa (rhodocetin), whereas related proteins accomplish dual receptor occupancy and bind GPVI and GPIbalpha (alboaggregin-A, alboluxin), or GPIbalpha and GPIa-IIa (aggretin). These latter venom proteins mimic physiological ligands, vWF or collagen, which also recognize more than one receptor. Similarly, metalloproteinase-disintegrin family proteins target GPlbalpha (mocarhagin, crotalin), GPVI (alborhagin) or GPIa-IIa (jararhagin), resulting in inhibition or induction of platelet aggregation by proteolytically dependent or independent mechanisms. Anti-thrombotics based on snake venom GPIIb-IIIa inhibitors have been investigated clinically, however analogous proteins recognizing GPIb-IX-V or GPVI are yet to be therapeutically exploited.
Vascular Biology Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton 3168, Australia. rob.andrews@med.monash.edu.au
Robert K
RK
Andrews
Elizabeth E
EE
Gardiner
Yang
Y
Shen
Michael C
MC
Berndt
D000818:Animals; D003094:Collagen / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D007930:Leucine / Q000737:chemistry / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D012910:Snake Venoms / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000378:metabolism
D037181:Lectins, C-Type; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D012910:Snake Venoms; C098341:platelet membrane glycoprotein VI; D014841:von Willebrand Factor; D003094:Collagen; D045726:Metalloproteases; D007930:Leucine