Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2.
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.
Watson
Aleksandra A
AA
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
Eble
Johannes A
JA
O'Callaghan
Chris A
CA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D003460:Crystallization; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D015539:Platelet Activation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D014757:Viper Venoms / Q000737:chemistry* / Q000302:isolation & purification; D014961:X-Ray Diffraction
D004220:Disulfides; D037181:Lectins, C-Type; D008024:Ligands; D021122:Protein Subunits; D014757:Viper Venoms; C112292:rhodocytin protein, Calloselasma rhodostoma