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Coordinación pleomórfica del cobre por el péptido amiloide-beta de la enfermedad de Alzheimer

Simon C Drew¹, Christopher J Noble, Colin L Masters

¹Department of Pathology, The University of Melbourne, Victoria 3010, Australia. sdrew@unimelb.edu.au

Journal of the American Chemical Society

|January 6, 2009

Resumen

Este estudio revela dos modos distintos de coordinación Cu2+ en los péptidos beta amiloide (Abeta) a pH fisiológico, lo que aclara la unión del cobre en la patogénesis de la enfermedad de Alzheimer. Estos hallazgos resuelven modelos contradictorios de las interacciones cobre-Abeta.

Área de la Ciencia:

Química biofísica y bioquímica.
Química de las metaloproteínas
La neurociencia es la neurociencia.

Sus antecedentes:

La enfermedad de Alzheimer está relacionada con el péptido beta amiloide (Abeta).
El entorno de coordinación de Cu ((2+) por Abeta es poco conocido, con numerosos modelos contradictorios.
Comprender las interacciones Cu2+) -Abeta es crucial para la investigación de la enfermedad de Alzheimer.

Objetivo del estudio:

Para resolver directamente el entorno de coordinación Cu(2+) en los péptidos Abeta.
Para diferenciar entre los modelos propuestos de Cu(2+) que se une a Abeta.
Para aclarar el papel de los residuos de aminoácidos específicos en la coordinación del cobre.

Principales métodos:

Espectroscopia de resonancia paramagnética de electrones de onda continua de frecuencia múltiple (CW-EPR). espectroscopia de resonancia paramagnética de electrones de onda continua de frecuencia múltiple.
Etiquetado específico del sitio (15) N y (13) C de los péptidos Abeta.
Simulaciones numéricas de resonancias superhiperfinas y espectroscopia de correlación de subniveles hiperfinos (HYSCORE).

Principales resultados:

Se identificaron dos modos de coordinación 3N1O Cu2+ distintos ({N(a) ((D1), O, N(epsilon) ((H6), N(epsilon) ((H13)} y {N(a) ((D1), O, N(epsilon) ((H6), N(epsilon) ((H14)) }) en un pH de 6 a 7.
Se observó un tercer modo de coordinación 3N1O que involucra a His6, His13 y His14 a un pH de 8.0.
Se confirmó que el oxígeno fenólico de Tyr10 no es un ligando clave en el rango de pH fisiológico.
El oxígeno carboxilado Asp1 fue identificado como un ligando ecuatorial en los modos de coordinación primarios.

Conclusiones:

El estudio resolvió directamente las interacciones del ligando Cu(2+) en Abeta, identificando dos modos de coordinación primarios.
Estos hallazgos proporcionan una visión crítica de la complejidad de las interacciones Cu(2+) / Abeta.
Los resultados ayudan a resolver las ambigüedades de larga data en la literatura con respecto a la unión del cobre a Abeta.

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