title: Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex.
abstract: How botulinum neurotoxins (BoNTs) cross the host intestinal epithelial barrier in foodborne botulism is poorly understood. Here, we present the crystal structure of a clostridial hemagglutinin (HA) complex of serotype BoNT/A bound to the cell adhesion protein E-cadherin at 2.4 angstroms. The HA complex recognizes E-cadherin with high specificity involving extensive intermolecular interactions and also binds to carbohydrates on the cell surface. Binding of the HA complex sequesters E-cadherin in the monomeric state, compromising the E-cadherin-mediated intercellular barrier and facilitating paracellular absorption of BoNT/A. We reconstituted the complete 14-subunit BoNT/A complex using recombinantly produced components and demonstrated that abolishing either E-cadherin- or carbohydrate-binding of the HA complex drastically reduces oral toxicity of BoNT/A complex in vivo. Together, these studies establish the molecular mechanism of how HAs contribute to the oral toxicity of BoNT/A.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
authors.forename: Kwangkook
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Division of Neuroscience, New England Primate Research Center, Southborough, MA 01772, USA.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
authors.forename: Shenyan
authors.initials: S
authors.lastname: Gu
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Anna Magdalena
authors.initials: AM
authors.lastname: Kruel
authors.affiliation: Centre for Biological Threats and Special Pathogens-Biological Toxins (ZBS3), Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Dorner
authors.affiliation: Northeastern Collaborative Access Team (NE-CAT) and Department of Chemistry and Chemical Biology, Cornell University, Building 436E, Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, IL 60439, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Perry
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Division of Neuroscience, New England Primate Research Center, Southborough, MA 01772, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA. r.jin@uci.edu.
authors.forename: Rongsheng
authors.initials: R
authors.lastname: Jin
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000235:genetics; D015820:Cadherins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006388:Hemagglutinins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D051379:Mice; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D015820:Cadherins; D006388:Hemagglutinins; D011994:Recombinant Proteins; D019274:Botulinum Toxins, Type A