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El papel del zinc en la agregación de polipéptidos amiloides de las islas humanas
Jeffrey R Brender1, Kevin Hartman, Ravi Prakash Reddy Nanga
1Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Journal of the American Chemical Society
|June 12, 2010
Resumen
El zinc inhibe significativamente la fibrilogénesis amiloide del polipéptido amiloide de las islas humanas (hIAPP), un factor clave en la diabetes tipo II. Este hallazgo sugiere un papel protector para el zinc en la prevención de la pérdida de células beta.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Investigación de la diabetes Investigación de la diabetes.
Sus antecedentes:
- La agregación del polipéptido amiloide de islotes humanos (hIAPP) está relacionada con la toxicidad de las células beta y la pérdida en la diabetes tipo II.
- El mecanismo que mantiene las concentraciones seguras de hIAPP dentro de los gránulos secretores sigue sin estar claro.
Objetivo del estudio:
- Para investigar el papel del zinc en la modulación de la fibrilogénesis amiloide de la hIAPP.
- Para aclarar los mecanismos estructurales y electrostáticos que subyacen al efecto inhibidor del zinc en la agregación de la hIAPP.
Principales métodos:
- Espectroscopia de Resonancia Magnética Nuclear (RMN) para determinar las estructuras de alta resolución.
- Los ensayos de fibrilogénesis in vitro se realizan a diferentes concentraciones de zinc y pH.
- Análisis de los efectos electrostáticos y estructurales de la unión de zinc.
Principales resultados:
- El zinc inhibe significativamente la fibrilogénesis amiloide de la hIAPP en concentraciones fisiológicamente relevantes.
- El zinc exhibe un doble efecto dependiente de la concentración en la cinética de la fibrilogénesis.
- Las estructuras de RMN confirman la unión de zinc a His18, causando una alteración localizada de la estructura secundaria.
Conclusiones:
- La unión del zinc a His18 inhibe la agregación de la hIAPP a través de interacciones electrostáticas y alteraciones estructurales.
- Esto proporciona un mecanismo potencial que vincula las mutaciones SLC30A8, el transporte de zinc y el riesgo de diabetes tipo II.
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