Activity of botulinum neurotoxin X and its structure when shielded by a non-toxic non-hemagglutinin protein
Year: 2024
Type: article
Abstract: Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex and the crystal structure of the isolated NTNH protein. Unexpectedly, the BoNT/X complex is stable and protease-resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents very weak ganglioside binding and exposed hydrophobic surfaces.
Source: Communications Chemistry
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: Burroughs Wellcome Fund, Diamond Light Source, Kempe Foundation, Cancerfonden, Knut och Alice Wallenbergs Stiftelse, Akademie Věd České Republiky, Vetenskapsrådet, Umeå Universitet, Kempestiftelserna, Stockholms Universitet, Science for Life Laboratory, Ipsen, National Institutes of Health, European Regional Development Fund, Ústav organické chemie a biochemie Akademie věd České republiky, National Institute of Neurological Disorders and Stroke, European Social Fund
Awards: G1172744205, G200293887, G291036901, G6481180838, G6558202982, G712881263, The Botulinum neurotoxins -structure and mechanism of the most potent toxins of all, G7632489701, Clostridial neurotoxins, deadly toxins that also can heal -How do these large proteins bind to, and then cross the membrane?, Biology and Engineering of Botulinum Neurotoxins., Targeted Delivery of Therapeutics into Motor Neurons for Post-exposure Treatment of Botulism
OpenAlex ID: W4401550330