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Bases estructurales de la regulación de la separasa humana por la seculina y la CDK1-ciclina B1
Jun Yu1, Pierre Raia1, Chloe M Ghent2
1Department of Molecular Biology, University of Geneva, Geneva, Switzerland.
Nature
|July 22, 2021
Resumen
La separasa humana, crucial para la segregación cromosómica, está regulada por los inhibidores de la securina y la CDK1-ciclina B1. Estos inhibidores utilizan motivos de seudosubstrato para bloquear la actividad de la separasa, asegurando una división celular precisa.
Área de la Ciencia:
- Biología celular
- Biología molecular
- La bioquímica
Sus antecedentes:
- La segregación cromosómica se basa en el complejo de cohesión, que es escindido por la separasa durante la anafase.
- La activación de la separasa está relacionada con la degradación de sus inhibidores, la securina y la ciclina B, pero los mecanismos reguladores siguen sin estar claros.
Objetivo del estudio:
- Elucidar los mecanismos moleculares por los cuales la securina y la CDK1-ciclina B1 inhiben la separasa humana.
- Proporcionar conocimientos estructurales sobre la regulación de la segregación cromosómica.
Principales métodos:
- Se empleó microscopía electrónica criogénica (cryo-EM) para determinar las estructuras de la separasa humana.
- Las estructuras se resolvieron para la separasa en complejo con securina y con CDK1-ciclina B1-CKS1.
Principales resultados:
- La separasa es inhibida por motivos de seudosubstrato que bloquean sus sitios catalíticos y de acoplamiento.
- Securin utiliza sus propios motivos de seudosubstrato, mientras que CDK1-ciclina B1 emplea los bucles desordenados intrínsecos de la separasa para la inhibición.
- La unión a la CDK1-ciclina B1 también posiciona un bucle autoinhibidor para bloquear tanto los sitios activos de la separasa como de la CDK1.
Conclusiones:
- La securina y la CDK1-ciclina B1 emplean diversos mecanismos basados en pseudo-substrato para inhibir la separasa.
- Los datos estructurales revelan cómo la CDK1-ciclina B1 utiliza las propias regiones desordenadas de la separasa para la regulación, incluida una interacción con la fosfoserina.
- Este estudio proporciona una base molecular para el control preciso de la segregación cromosómica por inhibidores de la separasa.
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