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Published on: September 28, 2018
Bases estructurales para la inhibición de la proteína receptor-tirosina fosfatasa-alfa por la dimerización
A M Bilwes1, J den Hertog, T Hunter
1Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature
|August 8, 1996
Resumen
La actividad de las fosfatasas de proteína-tirosina similares a los receptores (RPTP) está regulada por la dimerización. El análisis estructural revela que los segmentos N-terminales pueden bloquear el sitio activo, regulando a la baja la función RPTP.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La señalización celular de las células.
Sus antecedentes:
- Las fosfatasas de proteína-tirosina similares a los receptores (RPTP) son proteínas de membrana integrales que regulan los niveles de fosfotirosina.
- Su actividad catalítica y la regulación por los ligandos extracelulares permanecen en gran parte sin caracterizar.
Objetivo del estudio:
- Para aclarar la base estructural de la regulación RPTP.
- Para investigar el mecanismo de control de la actividad catalítica de RPTPalpha.
Principales métodos:
- Determinación de la estructura cristalina del dominio catalítico murino RPTPalpha de membrana-proximal (D1).
- Análisis de las desviaciones estructurales de los pliegues conocidos de PTP1B.
- Alineaciones de secuencias e integración de los datos de los estudios de los receptores del FEAG/CD45 en la quimera.
Principales resultados:
- Se identificaron desviaciones estructurales significativas en RPTPalphaD1, incluido un segmento de hélice-giro-hélice N-terminal y una hoja beta única.
- Se observa la inserción del segmento N-terminal en el sitio activo de un monómero D1 relacionado con la diada.
- Proporcionó evidencia de un mecanismo de bloqueo del sitio activo mediado por dimerización.
Conclusiones:
- Proponer que la dimerización de RPTP y el posterior bloqueo del sitio activo es un mecanismo clave para la regulación a la baja de RPTPalpha y otras RPTP.
- Sugiere una nueva vía reguladora para las RPTP independientes de los ligandos extracelulares.
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