Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation
The recent Nature Communications paper by the group of Volodymyr Korkhov (IMBB, ETHZ & PSI) in collaboration with the group of Richard Kammerer (PSI), provides insights into recognition of botulinum neurotoxin BoNT/A1 by its receptor SV2B, and into the pH-dependent conformational changes in the toxin relevant to its mechanism of action.
Botulinum neurotoxin A1 (BoNT/A1) is one of the most potent toxins, used as a major therapeutic agent. It is assumed that specific conformational rearrangements are critical for translocation of BoNT/A1 catalytic domain (LC) into the neuronal cytosol where it exerts its action by proteolytically cleaving SNARE proteins essential for synaptic vesicle function. Blocking the synaptic vesicle fusion to the presynaptic membrane at the neuromuscular junctions inhibits acetylcholine release, leading to muscle relaxation and paralysis. However, the precise molecular mechanism of neurotoxin translocation is not well understood.
A study led by the groups of Volodymyr Korkhov (Basavraj Khanppnavar, PSI & Institute of Molecular Biology and Biophysics, ETH Zurich) and Richard Kammerer (Oneda Leka, PSI) provides novel molecular insights into the steps preceding toxin translocation. The authors determined the cryo-EM structures of BoNT/A1 alone and in complex with its receptor, synaptic vesicle glycoprotein 2B (SV2B). In solution BoNT/A1 was found to adopt a unique semi-closed conformation. The toxin changes its structure into an open state upon receptor binding with the translocation domain (HN) and the LC domain remote from the membrane, suggesting that this conformation is incompatible with translocation. 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 HN close to the membrane, suggesting that a translocation-competent state of the toxin is required for successful LC transport into the neuronal cytosol. This study sets the stage for detailed investigations of the molecular mechanisms of neurotoxin recognition and translocation, with important implications not only for our understanding of how neurotoxins work, but also for development of novel neurotoxin-based therapeutics.
Link to the paper in external page 'Nature Communications'.