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Mecanismo de la activación de PARKIN inducida por la fosfo-ubiquitina

Tobias Wauer¹, Michal Simicek¹, Alexander Schubert¹

¹Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.

|July 11, 2015

Resumen

La estructura cristalina de PARKIN unido a la ubiquitina fosforilada revela cómo las mutaciones causan el Parkinsonismo. Este hallazgo explica la activación de PARKIN y sugiere nuevos objetivos terapéuticos para la enfermedad.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
La neurociencia es la neurociencia.

Sus antecedentes:

Las mutaciones en PARKIN (PARK2) y PINK1 (PARK6) causan el Parkinsonismo juvenil autosómico-recesivos (AR-JP).
PARKIN y PINK1 colaboran en la mitofagia para eliminar las mitocondrias dañadas.
PINK1 fosforila la ubiquitina y el dominio PARKIN Ubl, reclutando y activando PARKIN en las mitocondrias despolarizadas.

Objetivo del estudio:

Para dilucidar el mecanismo molecular del reclutamiento y activación de PARKIN por la ubiquitina fosforilada.
Para entender cómo las mutaciones asociadas a AR-JP afectan la función de PARKIN.

Principales métodos:

Cristalografía de rayos X de Pediculus humanus PARKIN complejo con ubiquitina Ser65-fosforilada (phosphoUb).

Principales resultados:

La estructura cristalina revela que el phosphoUb se une a una bolsa de fosfato conservado en PARKIN, lo que explica el reclutamiento y la activación.
La unión de PhosphoUb induce cambios conformacionales, liberando el dominio inhibidor Ubl y activando PARKIN.
Esta liberación de Ubl mediada por fosfoUb mejora aún más la fosforilación de Ubl por PINK1, estabilizando una conformación activa de PARKIN.

Conclusiones:

El dominio Ubl actúa como un elemento activador restringido liberado por el fosfoUb.
Este estudio aclara las bases estructurales de la activación de PARKIN y su papel en el parkinsonismo.
Identifica estrategias potenciales para el desarrollo de activadores PARKIN de pequeñas moléculas.

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