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Desvío químico de la catálisis de base general en la colesterolálisis de proteínas de erizo utilizando un sustrato
Daniel A Ciulla1, Michael T Jorgensen2, José-Luis Giner2
1Chemistry Department, Binghamton University (SUNY) , Binghamton, New York 13902, United States.
Journal of the American Chemical Society
|September 21, 2017
Resumen
Las proteínas de erizo utilizan el colesterol para la auto-escisión. Una proteína mutante, D303A, fue reactivada usando un colesterol modificado con un grupo hidroperoxido, revelando el efecto alfa
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Química de las proteínas
Sus antecedentes:
- Las proteínas de erizo son moléculas de señalización cruciales.
- Se someten a un procesamiento automático a través de la endoproteólisis autocatalizada.
- El colesterol actúa como un nucleófilo en este proceso, con D303 identificado como el catalizador base general.
Objetivo del estudio:
- Investigar el papel del residuo de aspartato conservado (D303) en el autoprocesamiento del erizo.
- Para explorar el mecanismo de activación del colesterol por D303.
- Caracterizar la actividad de los mutantes erizos con sustratos alternativos.
Principales métodos:
- Mutagénesis dirigida al sitio del residuo D303 en proteínas de erizo.
- Síntesis de un nuevo sustrato, el 3β-hidroperoxicolestano (3HPC).
- Evaluación de la actividad mutante del erizo utilizando colesterol y 3HPC.
Principales resultados:
- La mutación de D303 a alanina (D303A) redujo drásticamente la actividad de autoprocesamiento del erizo (> 10 ^ 4 veces).
- El mutante D303A mostró un rescate significativo de la actividad con 3HPC, un sustrato con un grupo hidroperoxido.
- Otros mutantes D303 (D303N, D303R, D303E) también mostraron diversos grados de actividad rescatada con 3HPC.
- La mayor reactividad de 3HPC se atribuyó al efecto alfa.
Conclusiones:
- El residuo D303 en las proteínas de erizo actúa como un catalizador de base general para la activación del colesterol.
- El efecto alfa, derivado del grupo hidroperoxido en 3HPC, mejora la nucleofilicidad y rescata la actividad mutante.
- Este estudio proporciona información sobre el mecanismo de autoprocesamiento del erizo y el papel de la nucleofilicidad del sustrato.
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