Crystal Structures of Botulinum Neurotoxin DC in Complex with Its Protein Receptors Synaptotagmin I and II

• Published in: Structure (London) Vol. 21; no. 9; pp. 1602 - 1611
• Main Authors: Berntsson, Ronnie Per-Arne, Peng, Lisheng, Svensson, Linda Marie, Dong, Min, Stenmark, Pål
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.09.2013
• Subjects: Amino Acid Sequence; Animals; Binding; Binding Sites; Botulinum Toxins - chemistry; Clostridium botulinum; Crystal structure; Crystallography, X-Ray; Direct current; Humans; Hydrogen Bonding; Models, Molecular; Molecular Sequence Data; Protein Interaction Domains and Motifs; Protein Structure, Quaternary; Protein Structure, Secondary; Proteins; Rats; Receptors; Recognition; Structural Homology, Protein; Synaptotagmin I - chemistry; Synaptotagmin II - chemistry; Toxins
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2013.06.026

Botulinum neurotoxins (BoNTs) can cause paralysis at exceptionally low concentrations and include seven serotypes (BoNT/A-G). The chimeric BoNT/DC toxin has a receptor binding domain similar to the same region in BoNT/C. However, BoNT/DC does not share protein receptor with BoNT/C. Instead, it shares synaptotagmin (Syt) I and II as receptors with BoNT/B, despite their low sequence similarity. Here, we present the crystal structures of the binding domain of BoNT/DC in complex with the recognition domains of its protein receptors, Syt-I and Syt-II. The structures reveal that BoNT/DC possesses a Syt binding site, distinct from the established Syt-II binding site in BoNT/B. Structure-based mutagenesis further shows that hydrophobic interactions play a key role in Syt binding. The structures suggest that the BoNT/DC ganglioside binding sites are independent of the protein receptor binding site. Our results reveal the remarkable versatility in the receptor recognition of the BoNTs. •A Syt binding site within the BoNT family is established in BoNT/DC•The crystal structure of a BoNT in complex with Syt-I•BoNT/DC has a distinctly different binding site for Syt than BoNT/B•The structures suggest three potential anchoring points to the neuronal membrane Berntsson et al. determine crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. The receptor complexes and mutational analysis help define the toxin’s binding site on the receptor and suggest three potential anchoring points to the neuronal membrane.