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Mecanismo de activación de parkin por PINK1
Christina Gladkova1, Sarah L Maslen1, J Mark Skehel1
1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Nature
|July 12, 2018
Resumen
La activación de la proteína de Parkin, crucial para la mitofagia y la prevención del parkinsonismo juvenil, implica reorganizaciones de dominio a gran escala. Este proceso libera el dominio catalítico, ofreciendo nuevos objetivos para el diseño de fármacos terapéuticos.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- La neurociencia
Sus antecedentes:
- Las mutaciones en parkin (PARK2/PRKN) y PINK1 (PARK6) causan parkinsonismo juvenil autosómico recesivo (AR-JP).
- Estas mutaciones conducen a defectos celulares en la mitofagia, el proceso de degradación de las mitocondrias dañadas.
- Parkin es una ligasa de ubiquitina E3 que requiere fosforilación mediada por PINK1 para su activación, pero el mecanismo sigue sin estar claro.
Objetivo del estudio:
- Para aclarar el mecanismo molecular de la activación de parkin por PINK1.
- Para entender cómo se resuelve la autoinhibición de parkin con la fosforilación.
- Identificar posibles objetivos terapéuticos para el AR-JP.
Principales métodos:
- Espectrometría de masas de intercambio de hidrógeno y deuterio (HDX-MS) para rastrear la activación de parkin en humanos.
- Determinación de la estructura cristalina de parkin humano fosforilado.
Principales resultados:
- HDX-MS reveló reorganizaciones de dominio a gran escala durante la activación de parkin.
- El dominio de tipo ubiquitina fosforilado (phospho-Ubl) se vuelve a unir al núcleo de parkin, liberando el dominio catalítico RING2.
- La estructura cristalina identificó el sitio de unión fosfo-Ubl en el dominio único de parkin (UPD) y reveló una región de enlace de elemento activador (ACT).
Conclusiones:
- La activación de Parkin implica una reorganización significativa del dominio, liberando el dominio catalítico RING2.
- Las mutaciones AR-JP se agrupan en el sitio de unión fosfo-Ubl y en el vinculante ACT, explicando el vínculo de la enfermedad.
- Los hallazgos proporcionan un mecanismo para la ubiquitinación del sustrato de parkin y sugieren estrategias para diseñar activadores de parkin.
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