Podoplanin is a transmembrane O-glycoprotein that binds to C-type lectin-like receptor 2 (CLEC-2). The O-glycan-dependent interaction seems to play crucial roles in various biological processes, such as platelet aggregation. Rhodocytin, a snake venom, also binds to CLEC-2 and aggregates platelets in a glycan-independent manner. To elucidate the structural basis of the glycan-dependent and independent interactions, we performed comparative crystallographic studies of podoplanin and rhodocytin in complex with CLEC-2. Both podoplanin and rhodocytin bind to the noncanonical "side" face of CLEC-2. There is a common interaction mode between consecutive acidic residues on the ligands and the same arginine residues on CLEC-2. Other interactions are ligand-specific. Carboxyl groups from the sialic acid residue on podoplanin and from the C terminus of the rhodocytin α subunit interact differently at this "second" binding site on CLEC-2. The unique and versatile binding modes open a way to understand the functional consequences of CLEC-2-ligand interactions.
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