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Title: Structure-function studies on Clostridium botulinum neurotoxins
Author: Davies, Jonathan
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2019
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Botulinum neurotoxins (BoNTs) are the deadliest proteins known and cause flacid paralysis through inhibition of acetylcholine release from motor neurons. Each BoNT consists of three domains: the binding domain, the translocation domain and the catalytic light chain. The binding domain is responsible for the targetting of neuronal cell membranes and is able to form a dual-receptor complex with cell-surface receptors. The BoNT is taken into the cell through endocytosis where the translocation domain acts to release the catalytic light chain into the cell cytosol. The light chain is then free to cleave one of the SNARE (soluble N-ethylmaleimide-sensitive-fusion-protein attachment protein receptor) proteins, inhibiting exocytosis and thus neurotransmitter release. BoNTs are categorised into serotypes (BoNT/A to /G) and subtypes (e.g. BoNT/A1) based on amino acid variations. BoNTs have many therapeutic uses including as a treatment for cervical dytonia, strabismus, and overactive bladder and the most common commercially available product consists of BoNT/A1. Subtle amino acid variations between BoNT subtypes may have a dramatic impact on the properties of the protein, some of which may be useful for the production of engineered BoNTs in the future. In this thesis, the crystal structures of the binding domains from BoNT/A1 to /A6 were determined to high resolution and their binding to the protein-receptor SV2 was investigated. The structures of full-length BoNTs in solution were also investigated to confirm whether multiple domain-organisations exist across BoNT serotypes. There are over 150 different BoNTs known and this work also includes a new open-access tool for identifying and retrieving information about specific BoNTs in a fast and easy way.
Supervisor: Subramanian, Vasanta ; Acharya, K-Ravi Sponsor: Ipsen Bioinnovation Limited
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available