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Assaying the Kinase Activity of LRRK2 in vitro
Published on: January 18, 2012
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Estructura de LRRK2 en la enfermedad de Parkinson y modelo de interacción de microtúbulos
C K Deniston1,2, J Salogiannis1,3, S Mathea4
1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Nature
|August 20, 2020
Resumen
Los filamentos de repetición de la quinasa 2 (LRRK2) ricos en leucina pueden bloquear el movimiento de las proteínas motoras en los microtúbulos. Los inhibidores que estabilizan una conformación abierta de LRRK2 reducen la formación de filamentos, ofreciendo una estrategia terapéutica para la enfermedad de Parkinson.
Área de la Ciencia:
- La neurociencia
- Biología estructural
- Biología molecular
Sus antecedentes:
- La quinasa de repetición rica en leucina 2 (LRRK2) es un gen clave en la patogénesis de la enfermedad de Parkinson.
- Se establece el papel de LRRK2 en el tráfico de membranas y la asociación de microtúbulos.
- Los datos estructurales limitados dificultan la comprensión de la función de LRRK2.
Objetivo del estudio:
- Para determinar la estructura de la mitad catalítica de LRRK2.
- Para modelar el LRRK2 asociado a los microtúbulos.
- Para aclarar el mecanismo de la interacción LRRK2-microtubular y su regulación por conformación de la quinasa.
Principales métodos:
- Cristalografía de rayos X o criogenización electromagnética para la determinación estructural.
- Tomografía criolectrónica para el modelado estructural in situ.
- Ensayos de motilidad in vitro con motores purificados y LRRK2.
- Ensayos basados en células para evaluar la formación de filamentos LRRK2 y los efectos inhibidores.
Principales resultados:
- Se informó de la estructura de la mitad catalítica de LRRK2.
- Desarrolló un modelo atómico de LRRK2 asociado a microtúbulos.
- Se ha demostrado que los filamentos LRRK2 bloquean la motilidad de la quinesina-1 y de la dineína-1.
- Se demostró que los inhibidores de la quinasa que estabilizan una conformación abierta reducen la formación de filamentos LRRK2 en las células.
Conclusiones:
- La conformación de LRRK2 regula su asociación de microtúbulos y su oligomerización.
- LRRK2 puede funcionar como un obstáculo físico para los motores basados en microtúbulos.
- Las estrategias terapéuticas dirigidas a la conformación LRRK2 pueden ser beneficiosas para la enfermedad de Parkinson.
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