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Regulación dual de BACH1 por las ligasas E3 del tipo SCF complementarias

Benedikt Goretzki¹, Maryam Khoshouei¹, Martin Schröder¹

¹Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland.

|December 10, 2024

Resumen

Este estudio revela cómo la proteína BACH1, un regulador del estrés oxidativo y el oncogén, es controlada por dos ligasas de ubiquitina. Un mecanismo de conmutación permite que FBXO22 o FBXL17 se unan a BACH1 dependiendo de su estado estructural, impactando el cáncer y los trastornos por estrés oxidativo.

Área de la Ciencia:

La bioquímica
Biología molecular
Biología celular

Sus antecedentes:

El dominio de amplio complejo, tramtrack y bric-à-brac (BTB) y el homólogo CNC 1 (BACH1) es un regulador clave del estrés oxidativo celular y un oncogén.
BACH1 está regulado post-traducionalmente por las ligasas de ubiquitina SCF^FBXO22 y SCF^FBXL17, pero el mecanismo de reconocimiento bajo estrés oxidativo es desconocido.

Objetivo del estudio:

Aclarar el mecanismo por el cual FBXO22 y FBXL17 reconocen BACH1 en condiciones de estrés oxidativo.
Comprender el mecanismo de conmutación de la ligasa que controla la regulación post-traducional de BACH1.

Principales métodos:

Análisis estructural del dimer BACH1 BTB y su interacción con FBXO22.
Investigar el impacto de las mutaciones asociadas al cáncer y las modificaciones de la cisteína en la estabilidad de BACH1 y la unión a la ligasa.
Caracterización del reconocimiento de BACH1 por FBXL17 como monómero.

Principales resultados:

FBXO22 reconoce un degrón cuaternario dentro de una hoja β intercambiada por dominio del dimero BACH1 BTB.
Las mutaciones en el cáncer y las modificaciones en la cisteína desestabilizan el degrón FBXO22, deteriorando la unión.
Estas modificaciones exponen un degradón distinto en la interfaz del dímero, permitiendo que FBXL17 se una al monómero BACH1.

Conclusiones:

Un mecanismo de conmutación de ligasa regula BACH1 por FBXO22 y FBXL17 basado en la estabilidad del dominio BTB.
Estos hallazgos proporcionan información mecanicista sobre la respuesta al estrés oxidativo.
El estudio puede informar estrategias terapéuticas para los trastornos relacionados con el estrés oxidativo y el cáncer.

Palabras clave:

BACH1 (en inglés)Las ligasas Cullin-RING Caja F En el caso de las personas físicas:En el caso de los vehículos de motor:Hemo por nitrosilación de S Modificación de la cisteína Interruptor de ligasa El estrés oxidativo

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