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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
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Evidencia de un mecanismo común de regulación de SIRT1 por activadores alostéricos
Basil P Hubbard1, Ana P Gomes, Han Dai
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|March 9, 2013
Resumen
Los compuestos que activan las sirtuinas (STAC) activan SIRT1 al interactuar con los motivos hidrofóbicos en sus sustratos. Un residuo específico de glutamato en SIRT1 es crucial para esta activación, revelando un mecanismo alostérico común para diversos STAC.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Investigación sobre el envejecimiento Investigación sobre el envejecimiento
Sus antecedentes:
- La desacetilasa SIRT1 es un objetivo clave para el tratamiento de enfermedades relacionadas con la edad.
- El mecanismo preciso de los compuestos activadores de sirtuinas (STAC) sigue siendo objeto de debate.
- Comprender el mecanismo de las STAC es crucial para desarrollar terapias efectivas.
Objetivo del estudio:
- Para aclarar el mecanismo molecular por el cual los STAC activan SIRT1.1.
- Identificar las características estructurales clave en SIRT1 y sus sustratos involucrados en la activación mediada por STAC.
- Determinar si existe un mecanismo de activación común para los STACs químicamente diversos.
Principales métodos:
- Investigó el papel de los motivos hidrofóbicos en los sustratos de SIRT1 (por ejemplo, PGC-1α, FOXO3a) en la unión de STAC.
- Utilizó la mutagénesis dirigida al sitio para sondear la función de aminoácidos específicos en SIRT1, particularmente Glu230).
- Evaluó los efectos metabólicos de los STAC en las células primarias que expresan el tipo salvaje frente a las variantes SIRT1 de activación defectuosa.
Principales resultados:
- Los motivos hidrofóbicos específicos dentro de los sustratos de SIRT1 son esenciales para la activación inducida por STAC.
- Un solo aminoácido, Glu(230) en el dominio N-terminal de SIRT1, es crítico para la activación por todos los andamios STAC probados.
- Los STAC no pudieron provocar efectos metabólicos en las células que expresan un mutante SIRT1 de activación defectuosa, lo que confirma la participación directa de SIRT1.
Conclusiones:
- SIRT1 puede ser activado directamente por los STAC a través de un mecanismo alostérico conservado.
- Los hallazgos resaltan la importancia de las regiones que interactúan con el sustrato y los residuos específicos como el Glu230) para la eficacia de STAC.
- Este estudio proporciona una base mecanicista para el desarrollo de nuevos fármacos dirigidos a SIRT1 para afecciones relacionadas con la edad.
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