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Mecanismo de transferencia del sitio de empalme de 5' para la activación del espliceosoma humano
Clément Charenton1, Max E Wilkinson1, Kiyoshi Nagai1
1MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ccharent@mrc-lmb.cam.ac.uk mwilkin@mrc-lmb.cam.ac.uk kn@mrc-lmb.cam.ac.uk.
Science (New York, N.Y.)
|April 13, 2019
Resumen
Las ideas estructurales revelan cómo se ensambla el espliceosoma. Las estructuras cryo-EM muestran la liberación de ribonucleoproteínas nucleares pequeñas U1 (snRNP) y la formación de hélices de U6 snRNA, pasos clave en la activación del spliceosome para el splicing de RNA.
Área de la Ciencia:
- Biología molecular
- Biología estructural
- La bioquímica
Sus antecedentes:
- El spliceosoma es una gran máquina molecular responsable del empalme del pre-ARNm en las eucariotas.
- El ensamblaje del espliceosoma implica interacciones dinámicas entre las pequeñas ribonucleoproteínas nucleares (snRNP) y el pre-ARNm.
- Comprender la base estructural del ensamblaje del espliceosoma es crucial para descifrar la regulación de la expresión génica.
Objetivo del estudio:
- Determinar las estructuras de alta resolución de los complejos clave del spliceosoma humano.
- Para aclarar los mecanismos estructurales subyacentes a la disociación de U1 snRNP y la formación del centro catalítico.
Principales métodos:
- Se utilizó la crio-microscopía electrónica (cryo-EM) para obtener estructuras del espliceosoma pre-B humano y del tri-snRNP.
- Se obtuvieron datos estructurales de alta resolución (3,3 Å y 2,9 Å) para los complejos.
Principales resultados:
- La estructura del complejo pre-B humano revela la interacción de U1 snRNP con la helicasa Prp28 antes de su disociación.
- El cierre dependiente de ATP de los dominios Prp28 libera el sitio de empalme 5 ' (5' SS) para emparejarse con la caja U6 ACAGAGA.
- Esta interacción desencadena la remodelación, lo que lleva a la activación de la helicasa Brr2 para el desenrollo del ARN snU4/U6.
Conclusiones:
- El estudio proporciona detalles a nivel atómico de la activación del espliceosoma, destacando el papel de las helicasas en la remodelación.
- Estos hallazgos ofrecen información sobre el proceso dinámico de ensamblaje y catálisis de los espliceosomas.
- Las estructuras allanan el camino para la comprensión de las enfermedades relacionadas con el spliceosoma y el desarrollo de terapias.
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