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Un atlas de las especificidades del sustrato para el quinoma serino/treonino humano
Jared L Johnson1,2, Tomer M Yaron1,2,3,4,5, Emily M Huntsman1,2
1Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Nature
|January 11, 2023
Resumen
Este estudio perfila la especificidad del sustrato de las proteínas humanas serina/treonina (Ser/Thr) quinasas, revelando diversas interacciones quinasas-sustrato y permitiendo la identificación de las quinasas responsables de numerosos eventos de fosforilación en las células humanas.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Proteomía
Sus antecedentes:
- La fosforilación de proteínas es una modificación crucial después de la traducción que regula numerosos procesos biológicos.
- Miles de sitios de fosforilación están vinculados a enfermedades humanas, pero las quinasas responsables a menudo son desconocidas.
- El genoma humano codifica más de 300 proteínas serina/treonina (Ser/Thr), cuyas especificidades de sustrato son en gran medida no caracterizadas.
Objetivo del estudio:
- Perfilar sistemáticamente la especificidad de la secuencia de sustrato del quinoma Ser/Thr humano.
- Identificar computacionalmente las quinases responsables de los sitios de fosforilación conocidos.
- Para analizar las respuestas de señalización celular y descubrir la complejidad de la vía.
Principales métodos:
- Se utilizaron bibliotecas de péptidos sintéticos para determinar experimentalmente las preferencias de sustrato para 303 quinasas Ser/Thr humanas.
- Desarrolló métodos computacionales para anotar los datos del fosfoproteoma con las relaciones cinasa-sustrato.
- Aplicó el conjunto de datos de todo el quínoma para analizar respuestas de señalización en varios contextos celulares.
Principales resultados:
- Descubrió especificidades de sustrato significativamente diversas en todo el quinoma Ser/Thr, impulsadas en gran medida por la selectividad negativa.
- Predijo con éxito las quinases para un gran número de sitios de fosforilación, con una alta precisión para los sitios caracterizados anteriormente.
- Reveló nuevas ideas sobre la complejidad de las vías de señalización y los mecanismos compensatorios en respuesta a los estímulos.
Conclusiones:
- Proporciona un recurso completo que detalla la especificidad del sustrato del quinoma Ser/Thr humano.
- Permite el mapeo preciso de los eventos de fosforilación a las quinasas específicas.
- Ilumina la dinámica de la señalización celular y ofrece una herramienta para comprender las vías biológicas y los mecanismos de la enfermedad.
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