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      Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex.

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          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.

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          A graphical user interface to the CCP4 program suite.

          Elizabeth Potterton, Peter Briggs, Maria Turkenburg … (2003)
          CCP4i is a graphical user interface that makes running programs from the CCP4 suite simpler and quicker. It is particularly directed at inexperienced users and tightly linked to introductory and scientific documentation. It also provides a simple project-management system and visualization tools. The system is readily extensible and not specific to CCP4 software.
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            Adherens junction: molecular architecture and regulation.

            Masatoshi Takeichi, Wenxiang Meng (2009)
            The adherens junction (AJ) is an element of the cell-cell junction in which cadherin receptors bridge the neighboring plasma membranes via their homophilic interactions. Cadherins associate with cytoplasmic proteins, called catenins, which in turn bind to cytoskeletal components, such as actin filaments and microtubules. These molecular complexes further interact with other proteins, including signaling molecules, rendering the AJs into highly dynamic and regulatable structures. The AJs of such nature contribute to the physical linking of cells, as well as to the regulation of cell-cell contacts, which is essential for morphogenesis and remodeling of tissues and organs. Thus, elucidating the molecular architecture of the AJs and their regulatory mechanisms are crucial for understanding how the multicellular system is organized.
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              Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling

              Buzz Baum, Marios Georgiou (2011)
              The epithelial cadherin (E-cadherin)–catenin complex binds to cytoskeletal components and regulatory and signaling molecules to form a mature adherens junction (AJ). This dynamic structure physically connects neighboring epithelial cells, couples intercellular adhesive contacts to the cytoskeleton, and helps define each cell’s apical–basal axis. Together these activities coordinate the form, polarity, and function of all cells in an epithelium. Several molecules regulate AJ formation and integrity, including Rho family GTPases and Par polarity proteins. However, only recently, with the development of live-cell imaging, has the extent to which E-cadherin is actively turned over at junctions begun to be appreciated. This turnover contributes to junction formation and to the maintenance of epithelial integrity during tissue homeostasis and remodeling.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Science
                Title: Science (New York, N.Y.)
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Electronic): 1095-9203
                ISSN (Print): 0036-8075
                Publication date (Electronic): Jun 20 2014
                Volume: 344
                Issue: 6190
                Affiliations
                [1 ] Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
                [2 ] Department of Microbiology and Immunobiology, Harvard Medical School, Division of Neuroscience, New England Primate Research Center, Southborough, MA 01772, USA.
                [3 ] Institut für Toxikologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
                [4 ] Centre for Biological Threats and Special Pathogens-Biological Toxins (ZBS3), Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany.
                [5 ] 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.
                [6 ] Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA. r.jin@uci.edu.
                Article
                Publisher Item ID: 344/6190/1405 Mid ID: NIHMS626968
                DOI: 10.1126/science.1253823
                PMC ID: 4164303
                PubMed ID: 24948737
                SO-VID: 4ee3f7c5-d80d-4cd4-9e51-92a53da6ab4b
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