5jlv
From Proteopedia
Receptor binding domain of Botulinum neurotoxin A in complex with human glycosylated SV2C
Structural highlights
FunctionBXA1_CLOBH 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 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. Publication Abstract from PubMedBotulinum neurotoxin serotype A1 (BoNT/A1), a licensed drug widely used for medical and cosmetic applications, exerts its action by invading motoneurons. Here we report a 2.0-A-resolution crystal structure of the BoNT/A1 receptor-binding domain in complex with its neuronal receptor, glycosylated human SV2C. We found that the neuronal tropism of BoNT/A1 requires recognition of both the peptide moiety and an N-linked glycan on SV2. This N-glycan-which is conserved in all SV2 isoforms across vertebrates-is essential for BoNT/A1 binding to neurons and for its potent neurotoxicity. The glycan-binding interface on SV2 is targeted by a human BoNT/A1-neutralizing antibody currently licensed as an antibotulism drug. Our studies reveal a new paradigm of host-pathogen interactions, in which pathogens exploit conserved host post-translational modifications, thereby achieving highly specific receptor binding while also tolerating genetic changes across multiple isoforms of receptors. N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A.,Yao G, Zhang S, Mahrhold S, Lam KH, Stern D, Bagramyan K, Perry K, Kalkum M, Rummel A, Dong M, Jin R Nat Struct Mol Biol. 2016 Jul;23(7):656-62. doi: 10.1038/nsmb.3245. Epub 2016 Jun, 13. PMID:27294781[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Clostridium botulinum | Homo sapiens | Large Structures | Bagramyan K | Dong M | Jin R | Kalkum M | Lam K | Mahrhold S | Perry K | Rummel A | Stern D | Yao G | Zhang S
