Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

Zheng Liu, Pyung-Gang Lee, Nadja Krez, Kwok-ho Lam, Hao Liu, Adina Przykopanski, Peng Chen, Guorui Yao, Sicai Zhang, Jacqueline M. Tremblay, Kay Perry, Charles B. Shoemaker, Andreas Rummel, Min Dong () and Rongsheng Jin ()
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Zheng Liu: University of California, Irvine
Pyung-Gang Lee: Boston Children’s Hospital
Nadja Krez: Hannover Medical School
Kwok-ho Lam: University of California, Irvine
Hao Liu: Boston Children’s Hospital
Adina Przykopanski: Hannover Medical School
Peng Chen: University of California, Irvine
Guorui Yao: University of California, Irvine
Sicai Zhang: Boston Children’s Hospital
Jacqueline M. Tremblay: Tufts Cummings School of Veterinary Medicine
Kay Perry: Cornell University, Argonne National Laboratory
Charles B. Shoemaker: Tufts Cummings School of Veterinary Medicine
Andreas Rummel: Hannover Medical School
Min Dong: Boston Children’s Hospital
Rongsheng Jin: University of California, Irvine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (HCE) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between HCE and SV2 provide the crucial location and specificity information for HCE to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, HCE exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications.

Date: 2023
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DOI: 10.1038/s41467-023-37860-8

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