6es1
Crystal structure of the binding domain from botulinum neurotoxin A2 bound to extracellular domain of human receptor SV2CCrystal structure of the binding domain from botulinum neurotoxin A2 bound to extracellular domain of human receptor SV2C
Structural highlights
Function[BXA2_CLOBO] Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of the three isoforms SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the '197-Gln-|-Arg-198' bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure (By similarity). [SV2C_HUMAN] Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission. Positively regulates vesicle fusion by maintaining the readily releasable pool of secretory vesicles (By similarity). Publication Abstract from PubMedBotulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 A) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic. Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding.,Gustafsson R, Zhang S, Masuyer G, Dong M, Stenmark P Toxins (Basel). 2018 Apr 12;10(4). pii: toxins10040153. doi:, 10.3390/toxins10040153. PMID:29649119[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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