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Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation
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Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation
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Journal Article
Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation
2025
Overview
Botulinum neurotoxin A1 (BoNT/A1) belongs to the most potent toxins and is used as a major therapeutic agent. Neurotoxin conformation is crucial for its translocation to the neuronal cytosol, a key process for intoxication that is only poorly understood. To gain molecular insights into the steps preceding toxin translocation, we determine cryo-EM structures of BoNT/A1 alone and in complex with its receptor synaptic vesicle glycoprotein 2B (SV2B). In solution, BoNT/A1 adopts a unique, semi-closed conformation. The toxin changes its structure into an open state upon receptor binding with the translocation domain (H
N
) and the catalytic domain (LC) remote from the membrane, suggesting translocation incompatibility. Under acidic pH conditions, where translocation is initiated, receptor-bound BoNT/A1 switches back into a semi-closed conformation. This conformation brings the LC and H
N
close to the membrane, suggesting that a translocation-competent state of the toxin is required for successful LC transport into the neuronal cytosol.
Translocation into neurons is crucial for BoNT/A1 action. Here, the authors show by single-particle cryo-EM that BoNT/A1 bound to its receptor SV2B switches its conformation from an open, translocation-incompatible to a semi-closed, translocation-competent state at acidic pH.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/57
/ 82/80
/ 82/83
/ Animals
/ Botulinum Toxins, Type A - chemistry
/ Botulinum Toxins, Type A - metabolism
/ Botulinum Toxins, Type A - ultrastructure
/ Cytosol
/ Humanities and Social Sciences
/ Humans
/ Membrane Glycoproteins - chemistry
/ Membrane Glycoproteins - metabolism
/ Membrane Glycoproteins - ultrastructure
/ Nerve Tissue Proteins - chemistry
/ Nerve Tissue Proteins - metabolism
/ Nerve Tissue Proteins - ultrastructure
/ Science
/ Switches
/ Toxins
