title: Botulinum neurotoxin is shielded by NTNHA in an interlocked complex.
abstract: Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum-contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics.
authors.affiliation: Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shenyan
authors.initials: S
authors.lastname: Gu
authors.forename: Sophie
authors.initials: S
authors.lastname: Rumpel
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Jasmin
authors.initials: J
authors.lastname: Strotmeier
authors.forename: Hans
authors.initials: H
authors.lastname: Bigalke
authors.forename: Kay
authors.initials: K
authors.lastname: Perry
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shoemaker
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
authors.forename: Rongsheng
authors.initials: R
authors.lastname: Jin
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary
chemical_list: D001426:Bacterial Proteins; D046912:Multiprotein Complexes; D019274:Botulinum Toxins, Type A