PMID:15665869

Citation	Fukuda, K, Doggett, T, Laurenzi, IJ, Liddington, RC and Diacovo, TG (2005) The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation. Nat. Struct. Mol. Biol. 12:152-9
Abstract	Botrocetin is a snake venom protein that enhances the affinity of the A1 domain of plasma von Willebrand factor (vWF) for the platelet receptor glycoprotein Ibalpha (GPIbalpha), an event that contributes to bleeding and host death. Here we describe a kinetic and crystallographic analysis of this interaction that reveals a novel mechanism of affinity enhancement. Using high-temporal-resolution microscopy, we show that botrocetin decreases the GPIbalpha off-rate two-fold in both human and mouse complexes without affecting the on-rate. The key to this behavior is that, upon binding of GPIbalpha to vWF-A1, botrocetin prebound to vWF-A1 makes no contacts initially with GPIbalpha, but subsequently slides around the A1 surface to form a new interface. This two-step mechanism and flexible coupling may prevent adverse alterations in on-rate of GPIbalpha for vWF-A1, and permit adaptation to structural differences in GPIbalpha and vWF in several prey species.
Links	PubMed Online version:10.1038/nsmb892
Keywords	Amino Acid Sequence; Animals; Binding Sites; Blood Platelets/chemistry; Blood Platelets/drug effects; Blood Platelets/metabolism; Crotalid Venoms/chemistry; Crotalid Venoms/pharmacology; Crystallography, X-Ray; Humans; Kinetics; Mice; Models, Molecular; Molecular Sequence Data; Platelet Adhesiveness; Platelet Aggregation/drug effects; Platelet Glycoprotein GPIb-IX Complex/chemistry; Platelet Glycoprotein GPIb-IX Complex/metabolism; Protein Binding; Protein Structure, Tertiary; Sequence Alignment; von Willebrand Factor/chemistry; von Willebrand Factor/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
BOTJA:VM3B		GO:0035893: negative regulation of platelet aggregation in other organism	ECO:0000314:		P		A higher percentage of platelets are activated when exposed to botrocetin than when not (Figure 5). This chemical introduced by Gaboon Vipers causes hemorrhaging.	complete CACAO 6555
BOTJA:VM3B	involved_in	GO:0035893: negative regulation of platelet aggregation in other organism	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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