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El control de la adenilación mediante la obstrucción del sitio activo intra o intermolecular en las proteínas Fic

Philipp Engel¹, Arnaud Goepfert, Frédéric V Stanger

¹Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

|January 24, 2012

Resumen

Las proteínas fic regulan la señalización celular al catalizar la adenilación. Una hélice inhibidora conservada (α(inh)) obstruye el sitio de unión al ATP, controlando esta actividad en todos los dominios de la vida.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Biología celular Biología celular.

Sus antecedentes:

Las proteínas fic, definidas por el dominio FIC, catalizan la adenilación de proteínas (AMPilación).
Las proteínas bacterianas de Fic pueden causar la muerte celular por adenilizar las GTPasas de mamíferos.
La regulación de la actividad de adenilación de la proteína Fic es poco conocida en todos los ámbitos de la vida.

Objetivo del estudio:

Para dilucidar el mecanismo conservado que regula la adenilación mediada por el dominio FIC.
Investigar el papel de una α-hélice inhibidora (α(inh)) en el control de la actividad de la proteína Fic.
Para determinar la conservación evolutiva de este mecanismo de regulación.

Principales métodos:

Análisis estructural y funcional de las proteínas Fic, incluyendo VbhT y VbhA de Bartonella schoenbuchensis.
Análisis bioquímicos para evaluar la actividad de adenilación.
Modelado de homología estructural de proteínas Fic anotadas.

Principales resultados:

Una α-hélice inhibidora conservada (α(inh)) con un motivo (S/T)XXXE(G/N) obstruye el sitio de unión al ATP, regulando la adenilación.
El glutamato invariable en el motivo α(inh) compite con el ATP.
Se observó la represión intermolecular por la antitoxina VbhA y la inhibición intramolecular por extensiones α (((inh).
Las mutaciones en el motivo inhibidor aumentaron significativamente la actividad de adenilación.
El modelado de homología sugiere que este mecanismo inhibidor se conserva en ~90% de los dominios FIC en todos los dominios de vida y virus.

Conclusiones:

La adenilización del dominio FIC está universalmente controlada por la obstrucción del sitio de unión al ATP a través de una hélice α inhibidora conservada.
Este mecanismo regulador es antiguo y generalizado, se encuentra en todos los dominios de la vida y los virus.
Las futuras investigaciones deberían centrarse en cómo los factores celulares modulan esta inhibición.

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