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Published online before print June 26, 2008, 10.1110/ps.035568.108
Protein Science (2008), 17:1611-1616. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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PROTEIN STRUCTURE REPORT

Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2

Aleksandra A. Watson1, Johannes A. Eble2, and Chris A. O'Callaghan1

1 Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom
2 Center for Molecular Medicine, Department of Vascular Matrix Biology, Excellence Cluster Cardio-Pulmonary System, Frankfurt University Hospital, 60590 Frankfurt am Main, Germany

(RECEIVED April 10, 2008; FINAL REVISION June 14, 2008; ACCEPTED June 16, 2008)

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 Å 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 ({alpha}β)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 ({alpha}β)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.

Keywords: rhodocytin; C-type lectin; CLEC-2; CLEC1b; platelets; thrombosis; aggretin


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