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Binding of the snake venom protein rhodocytin to CLEC-2, a receptor on the surface of human platelets, initiates a signaling cascade leading to platelet activation and aggregation. We have previously solved the structure of CLEC-2. The 2.4 A resolution crystal structure of rhodocytin presented here demonstrates that it is the first snake venom or other C-type lectin-like protein to assemble as a non-disulfide linked (alphabeta)(2) tetramer. Rhodocytin is highly adapted for interaction with CLEC-2 and displays a concave binding surface, which is highly complementary to the experimentally determined binding interface on CLEC-2. Using computational dynamic methods, surface electrostatic charge and hydrophobicity analyses, and protein-protein docking predictions, we propose that the (alphabeta)(2) rhodocytin tetramer induces clustering of CLEC-2 receptors on the platelet surface, which will trigger major signaling events resulting in platelet activation and aggregation.

Original publication

DOI

10.1110/ps.035568.108

Type

Journal article

Journal

Protein Sci

Publication Date

09/2008

Volume

17

Pages

1611 - 1616

Keywords

Amino Acid Sequence, Animals, Binding Sites, Blood Platelets, Computational Biology, Computer Simulation, Crystallization, Dimerization, Disulfides, Humans, Hydrophobic and Hydrophilic Interactions, Lectins, C-Type, Ligands, Models, Molecular, Molecular Sequence Data, Molecular Weight, Platelet Activation, Protein Binding, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits, Sequence Homology, Amino Acid, Static Electricity, Viper Venoms, X-Ray Diffraction