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Conservación estructural y funcional de dominios clave en los receptores InsP3 y de ryanodina
Min-Duk Seo1, Saroj Velamakanni, Noboru Ishiyama
1Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Ontario M5G 1L7, Canada.
Nature
|January 31, 2012
Resumen
Los receptores de inositol-1,4,5-trisfosfato (InsP3Rs) y los receptores de ryanodina (RyRs) son canales de calcio intracelulares. Este estudio revela mecanismos de activación conservados entre InsP3Rs y RyRs, que involucran interfaces de dominio cruciales para el encierro de canales de calcio.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Biología Estructural Biología estructural.
Sus antecedentes:
- Los receptores de inositol-1,4,5-trisfosfato (InsP3Rs) y los receptores de ryanodina (RyRs) son canales críticos de Ca2+ intracelulares tetraméricos.
- Sus dominios porosos están regulados por grandes estructuras citosólicas, con el gating InsP3R iniciado por la unión InsP3 y que requiere un dominio supresor (SD).
- Comprender la base estructural de su activación es clave para descifrar la señalización celular del calcio.
Objetivo del estudio:
- Para aclarar los mecanismos estructurales subyacentes a la activación de InsP3Rs y RyRs.
- Para comparar las vías de activación conservadas entre estas dos importantes familias de canales de calcio.
- Identificar las interfaces y dominios clave involucrados en el encierro alostérico de InsP3Rs y RyRs.
Principales métodos:
- Determinadas estructuras de alta resolución (3.0-3.6 Å) de la región amino-terminal (NT) de la rata InsP3R1, tanto con como sin unión a InsP3.
- Se utilizaron estudios de mutagénesis para confirmar la importancia funcional de las interfaces identificadas.
- Empleó experimentos de intercambio de dominio entre InsP3R y RyR para probar la función conservada.
Principales resultados:
- Se identificaron dos interfaces discretas (α y β) entre el núcleo de unión InsP3 (IBC) y el dominio supresor (SD) en InsP3R1 NT.
- Estas interfaces y arreglos de dominio son muy similares a los que se encuentran en RyR1, lo que indica una organización estructural conservada.
- La mutagenesis y el intercambio de dominio confirmaron el papel crítico de la interfaz α en la activación y revelaron la conservación funcional entre InsP3R y RyR.
Conclusiones:
- Los mecanismos de activación de InsP3Rs y RyRs se conservan, lo que implica la modulación alostérica de las interfaces de dominio dentro de la región N-terminal.
- La unión de ligandos (InsP3) o las mutaciones asociadas a la enfermedad inducen cambios conformacionales que reorientan los dominios clave, en última instancia, cerrando el poro Ca2+.
- Este estudio proporciona un marco estructural unificado para comprender el encierro de estos canales de calcio intracelulares esenciales.
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