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Bases moleculares para la interrupción de la adhesión de la E-cadherina por la neurotoxina botulínica del complejo A
Kwangkook Lee1, Xiaofen Zhong2, Shenyan Gu1
1Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
Science (New York, N.Y.)
|June 21, 2014
Resumen
La neurotoxina botulínica (BoNT / A) atraviesa la barrera intestinal utilizando la hemaglutinina (HA) que se une a la E-cadherina y los carbohidratos. Esta interacción compromete las uniones celulares, lo que permite la absorción de toxinas y la toxicidad oral.
Área de la Ciencia:
- Biología molecular La biología molecular.
- Biología estructural Biología estructural.
- Microbiología Microbiología.
Sus antecedentes:
- El mecanismo de la neurotoxina botulínica (BoNT) que atraviesa la barrera intestinal en el botulismo transmitido por los alimentos no está claro.
- Las BoNT son potentes neurotoxinas producidas por la bacteria Clostridium botulinum.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular por el cual la hemaglutinina (HA) de BoNT/A facilita la absorción intestinal.
- Para determinar la base estructural de la interacción de HA con las células huésped.
Principales métodos:
- Cristalografía de rayos X para determinar la estructura del complejo BoNT/A HA unido a la E-cadherina.
- Producción recombinante del complejo completo de BoNT/A.
- Ensayos de toxicidad oral in vivo en un modelo de ratón.
Principales resultados:
- La estructura cristalina reveló la unión específica del complejo HA a la E-cadherina y los carbohidratos de la superficie celular.
- La unión de HA a la E-cadherina la secuestra en un estado monomérico, interrumpiendo las uniones intercelulares.
- La interrupción de la unión de la HA a la E-cadherina o a los carbohidratos redujo significativamente la toxicidad oral de BoNT/A in vivo.
Conclusiones:
- El complejo BoNT/A HA utiliza la doble unión (E-cadherina y carbohidratos) para romper la barrera epitelial intestinal.
- Este mecanismo molecular explica cómo los HAs contribuyen a la toxicidad oral de BoNT/A, proporcionando un objetivo para las intervenciones terapéuticas.
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