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Evolución de las proteínas. La degeneración generalizada y la epistasis en una interfaz proteína-proteína

Anna I Podgornaia¹, Michael T Laub²

¹Computational & Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Science (New York, N.Y.)

|February 7, 2015

Resumen

Los investigadores mapearon el espacio de secuencia funcional de la proteína quinasa PhoQ de Escherichia coli, revelando una extensa degeneración y efectos dependientes del contexto (epistasis) en la interfaz PhoQ-PhoP. Esto probablemente restringe la evolución de PhoQ, lo que resulta en una menor diversidad de ortólogos que las variantes funcionales.

Área de la Ciencia:

Biología Molecular Biología Molecular
Ingeniería de proteínas Ingeniería de proteínas.
Biología de Sistemas Biología de Sistemas.

Sus antecedentes:

El mapeo del espacio de secuencia de proteínas es crucial para comprender la función y la evolución de las proteínas.
La proteína quinasa PhoQ reconoce su sustrato PhoP, una interacción crítica en la señalización bacteriana.
Comprender la relación secuencia-función en PhoQ es esencial para descifrar sus mecanismos reguladores.

Objetivo del estudio:

Mapear sistemáticamente el espacio de secuencia funcional de los residuos clave en Escherichia coli PhoQ.
Para investigar el grado de degeneración y epistasis en la interfaz PhoQ-PhoP.
Para entender cómo la conectividad del espacio de secuencia limita la evolución de PhoQ.

Principales métodos:

Generación de una biblioteca completa de 160.000 variantes PhoQ en cuatro posiciones clave.
Utilizando un proceso de selección en dos pasos junto con la secuenciación de próxima generación.
Análisis de las relaciones secuencia-función e identificación de variantes funcionales.

Principales resultados:

Identificó 1659 variantes PhoQ funcionales de la biblioteca generada.
Se reveló una extensa degeneración en la interfaz PhoQ-PhoP, lo que indica que múltiples secuencias pueden producir proteínas funcionales.
Se observó una epistasis significativa, donde el efecto de las sustituciones de aminoácidos depende en gran medida de su contexto circundante.

Conclusiones:

La epistasis y el código genético crean una conectividad estructurada de variantes funcionales en el espacio de secuencia PhoQ.
Esta conectividad probablemente impone restricciones a la trayectoria evolutiva de PhoQ.
La diversidad observada de los ortólogos PhoQ es significativamente menor que la diversidad potencial de las variantes PhoQ funcionales.

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