El acoplamiento dinámico entre los dominios SH2 y SH3 de c-Src y Hck subyace a su inactivación por fosforilación de tirosina en el C-terminal
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Published on: September 28, 2018
M A Young1, S Gonfloni, G Superti-Furga
1Laboratories of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Cell
|April 13, 2001
Resumen
La fosforilación de las cinasas Src.
Área de la Ciencia:
- Bioquímica y Biología Molecular.
- La señalización celular de las células.
- Investigación de la proteína quinasa Investigación de la proteína quinasa
Sus antecedentes:
- Las cinasas Src son reguladores cruciales de las vías de señalización celular.
- Su actividad está estrictamente controlada por los dominios reguladores, incluidos los dominios SH2 y SH3.
- La fosforilación de la tirosina en el extremo C-terminal juega un papel clave en la regulación de la actividad de la Src kinasa.
Objetivo del estudio:
- Investigar el impacto de la fosforilación de la tirosina C-terminal en la dinámica molecular de las quinasas Hck y c-Src.
- Para aclarar el papel del conector SH2-SH3 en la regulación de la activación de la quinasa.
- Comprender el mecanismo por el cual la fosforilación de la cola influye en el acoplamiento de dominios.
Principales métodos:
- Se emplearon simulaciones de dinámica molecular para estudiar el comportamiento de las quinasas Hck y c-Src.
- Se simularon los efectos de la desfosforilación de la terminación C y las mutaciones del conector SH2-SH3.
- Se realizó un análisis mutacional de c-Src en la levadura Schizosaccharomyces pombe.
Principales resultados:
- Los dominios SH2 y SH3 de las quinasas Src inactivas están fuertemente acoplados por el conector, lo que dificulta la activación.
- La desfosforilación de la cola C-terminal reduce el acoplamiento del dominio SH2-SH3.
- La mutación del conector SH2-SH3 con glicina activa el c-Src, lo que sugiere una función reguladora.
Conclusiones:
- El conector SH2-SH3 actúa como un mecanismo inducible de 'bloqueo instantáneo'.
- La fosforilación de cola sujeta los dominios SH2 y SH3, manteniendo la inactividad de la quinasa.
- La liberación de la fosforilación de la cola permite la flexibilidad, facilitando la activación de la quinasa.
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