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Bases estructurales para el acoplamiento entre las compuertas de activación e inactivación en los canales K (((+)
Luis G Cuello1, Vishwanath Jogini, D Marien Cortes
1Department of Biochemistry and Molecular Biology, The University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA.
Nature
|July 9, 2010
Resumen
La interacción entre la activación y la inactivación del canal K (((+) es impulsada mecánicamente por los movimientos de la cadena lateral Phe 103. Estos movimientos desestabilizan el filtro de selectividad, causando la inactivación del canal e impactando la cinética de la puerta.
Área de la Ciencia:
- La biofísica es la biofísica.
- Biología Estructural Biología estructural.
- Fisiología Molecular Fisiología Molecular
Sus antecedentes:
- Los canales de potasio (K(+)) son cruciales para la señalización eléctrica celular.
- Las puertas de activación e inactivación acopladas son propiedades funcionales clave de los canales K (((+).
- Estudios previos demostraron el acoplamiento a través de los efectos iónicos y la accesibilidad de la cisteína.
Objetivo del estudio:
- Para aclarar los mecanismos estructurales que vinculan la activación y la inactivación del canal K (((+).
- Para identificar los residuos y movimientos específicos responsables de desencadenar la inactivación.
- Para investigar el papel de Phe 103 en el encierro del canal KcsA.
Principales métodos:
- Análisis de múltiples estructuras cristalinas de KcsA en varios estados abiertos.
- Simulaciones de dinámica molecular para calcular las energías de interacción.
- Mutagénesis dirigida al sitio (F103A, F103C, F103W) para evaluar los efectos funcionales.
- Comparación con el mutante del canal K (((+) de Shaker (I470A).
Principales resultados:
- Los movimientos de la puerta del haz interno, específicamente la rotación de la hélice TM2, hacen que Phe 103 se incline.
- La inclinación de Phe 103 desestabiliza el filtro de selectividad a través de interacciones con la hélice de poro y los residuos vecinos.
- Las mutaciones en la posición 103 muestran efectos dependientes del tamaño en la cinética de inactivación.
- La dinámica molecular confirma interacciones favorables entre Phe 103 y los residuos circundantes en estado abierto.
Conclusiones:
- Phe 103 reorganizaciones de la cadena lateral mecánicamente activación y inactivación de pareja en KcsA.
- Es probable que este mecanismo se extienda a otras familias de canales K (((+).
- El acoplamiento alostérico se basa en la deformación mecánica propagada a través de contactos estéricos.
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