title: Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation.
abstract: Clostridium botulinum produces seven antigenically distinct neurotoxins [C. botulinum neurotoxins (BoNTs) A-G] sharing a significant sequence homology. Based on sequence and functional similarity, it was believed that their three-dimensional structures will also be similar. Indeed, the crystal structures of BoNTs A and B exhibit similar fold and domain association where the translocation domain is flanked on either side by binding and catalytic domains. Here, we report the crystal structure of BoNT E holotoxin and show that the domain association is different and unique, although the individual domains are similar to those of BoNTs A and B. In BoNT E, both the binding domain and the catalytic domain are on the same side of the translocation domain, and all three have mutual interfaces. This unique association may have an effect on the rate of translocation, with the molecule strategically positioned in the vesicle for quick entry into cytosol. Botulism, the disease caused by BoNT E, sets in faster than any other serotype because of its speedy internalization and translocation, and the present structure offers a credible explanation. We propose that the translocation domain in other BoNTs follows a two-step process to attain translocation-competent conformation as in BoNT E. We also suggest that this translocation-competent conformation in BoNT E is a probable reason for its faster toxic rate compared to BoNT A. However, this needs further experimental elucidation.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Desigan
authors.initials: D
authors.lastname: Kumaran
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Eswaramoorthy
authors.forename: William
authors.initials: W
authors.lastname: Furey
authors.forename: Jorge
authors.initials: J
authors.lastname: Navaza
authors.forename: Martin
authors.initials: M
authors.lastname: Sax
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001905:Botulinum Toxins / Q000737:chemistry* / Q000378:metabolism; D003014:Clostridium botulinum / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D009498:Neurotoxins; D001905:Botulinum Toxins; C096326:botulinum toxin type E