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Dos aminoácidos dentro del nudillo del primer dedo de zinc especifican la activación del elemento de respuesta del
M Danielsen1, L Hinck, G M Ringold
1Department of Pharmacology, Stanford University School of Medicine, California 94305.
Cell
|June 30, 1989
Resumen
Los aminoácidos específicos en los receptores de esteroides determinan la activación del gen diana. Pequeños cambios en el primer dedo de zinc permiten a los receptores unirse a diferentes elementos de respuesta del ADN, revelando mecanismos clave en la regulación génica.
Área de la Ciencia:
- Biología molecular La biología molecular.
- Genética La genética.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los receptores de esteroides regulan la expresión génica a través de secuencias específicas de ADN.
- El dominio de unión al ADN, que forma dos dedos de zinc, es crucial para esta especificidad.
- Los elementos estructurales precisos que dictan el reconocimiento del gen objetivo siguen siendo incompletamente entendidos.
Objetivo del estudio:
- Identificar los residuos específicos de aminoácidos responsables de la especificidad de unión al ADN de los receptores de glucocorticoides (GR) y los receptores de estrógenos (ER).
- Investigar el papel del primer dedo de zinc en la discriminación entre los elementos de respuesta hormonal (ERH) estrechamente relacionados.
- Explorar cómo las alteraciones estructurales en el dominio de unión al ADN afectan la función del receptor y el reconocimiento de HRE.
Principales métodos:
- Mutagénesis dirigida al sitio para crear construcciones quiméricas GR y ER.
- Los ensayos del gen reportero miden la activación transcripcional de los promotores que contienen GRE y ERE.
- Análisis de la estructura y función del dominio de unión al ADN.
Principales resultados:
- Dos aminoácidos específicos dentro del primer dedo de zinc de los receptores de esteroides son críticos para discriminar entre sus elementos de respuesta afines.
- Los receptores quiméricos con dominios alterados del primer dedo mostraron una especificidad de unión al ADN alterada.
- Las modificaciones en la región del nudillo del primer dedo afectaron significativamente el reconocimiento de secuencias.
Conclusiones:
- Los aminoácidos identificados en el primer dedo de zinc son los principales determinantes de la especificidad de unión al ADN del receptor de esteroides.
- El dominio más amplio de unión al ADN proporciona un contexto estructural esencial para evitar interacciones no específicas del ADN.
- Estos hallazgos ofrecen información sobre los mecanismos moleculares subyacentes a la activación selectiva de genes por las hormonas esteroides.
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