9qcm
Botulinum neurotoxin type B1, 14-subunit, Large Progenitor Toxin Complex (L-PTC)
Structural highlights
FunctionBXB_CLOBK Botulinum toxin causes flaccid paralysis by inhibiting neurotransmitter (acetylcholine) release from the presynaptic membranes of nerve terminals of eukaryotic host skeletal and autonomic nervous system, with frequent heart or respiratory failure. Precursor of botulinum neurotoxin B which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins found in synaptic vesicles. Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them. Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway. When the pH of the toxin-containing endosome drops a structural rearrangement occurs so that the N-terminus of the HC forms pores that allows the light chain (LC) to translocate into the cytosol. Once in the cytosol the disulfide bond linking the 2 subunits is reduced and LC cleaves its target protein on synaptic vesicles, preventing their fusion with the cytoplasmic membrane and thus neurotransmitter release (By similarity).[UniProtKB:P10844] Has proteolytic activity. After translocation into the eukaryotic host cytosol, LC hydrolyzes the '76-Gln-|-Phe-77' bond in synaptobrevin-2/VAMP2, blocking neurotransmitter release (By similarity).[UniProtKB:P10844] Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into host cytosol. Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (RBD). The RBD is responsible for the adherence of the toxin to the cell surface. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and host synaptotagmin-1 and -2 (SYT1 and SYT2) which bind simultaneously to adjacent but separate sites at the tip of the HC. The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site; it may also prevent premature LC dissociation from the translocation channel and protect toxin prior to translocation (By similarity). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity).[UniProtKB:P10844] Publication Abstract from PubMedBotulinum neurotoxin serotype B1 (BoNT/B) is a highly potent neurotoxin and therapeutic agent. Here, we present the structure of the complete 14-subunit (780 kDa) progenitor toxin complex (L-PTC) and of five subcomplexes. The structures show how the toxin interacts with its associated components in their role to protect and deliver BoNT/B across epithelial barriers. Each subcomplex, including the M-PTC, M-PTC-HA70, NTNH-HA70, and HA70 trimer, provides detailed understanding of the assembly mechanism, in which the NTNH-nLoop adopts a unique fold that locks the M-PTC into a central pore formed by HA70. The HA subcomplex presents a tripod architecture with flexible legs that may adapt to the rugged cell surface. Mass photometry reveals the pH dependence of BoNT/B release from the complex which is unexpectedly influenced by the presence of HA70. This study provides the complete L-PTC structure, offering insights into its assemblage and supporting the development of countermeasures and therapeutic applications. Structure of the complete 14-subunit botulinum neurotoxin B complex reveals a unique anchoring through the narrow central pore of HA70.,Krc A, Kosenina SP, Nowakowska MB, Masuyer G, Stenmark P Sci Adv. 2025 Aug 29;11(35):eadx5058. doi: 10.1126/sciadv.adx5058. Epub 2025 Aug , 27. PMID:40864696[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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