Researchers Uncover New Potential for Botulinum Neurotoxin E in Therapeutic and Cosmetic Applications

Posted By Madilyn Moeller, Thursday, May 4, 2023


A team of researchers from the University of California, Irvine, has revealed the first crystal structures of the receptor-binding domain of botulinum neurotoxin E (BoNT/E) in complex with its human neuronal receptors, synaptic vesicle glycoprotein 2A (SV2A). This structure and other findings in the new study could be harnessed to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments.

Published in Nature Communications, the study, titled, "Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2," reveals a novel 3D structure that shows how BoNT/E simultaneously recognizes both specific protein segments and an N-glycan of its host receptor SV2A for effective neuronal binding and uptake.

This mechanism is distinct from how BoNT/A (e.g. Botox) or BoNT/B (e.g. Myobloc) recognize their human receptors. Additionally, the team's findings demonstrate how BoNT/E is able to detect subtle differences in the primary sequences of three closely related SV2 isoforms, resulting in high selectivity towards SV2A and SV2B, but not SV2C, as its receptors.

"Since both BoNT/E and BoNT/A piggyback on human SV2 as receptors to sneak into neurons, we used to believe that they should use the same tactics. Surprisingly, our new crystal structure reveals that they, in fact, exploit distinct mechanisms to recognize SV2 for cell entry, which could partly explain the unique pharmacological and clinical profiles of BoNT/E," said Rongsheng Jin, Ph.D., professor in the Department of Physiology & Biophysics in the UCI School of Medicine.

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