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Cómo la insulina activa su sitio de unión primario en el receptor de insulina
John G Menting1, Jonathan Whittaker, Mai B Margetts
1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
Nature
|January 11, 2013
Resumen
Los investigadores revelan el receptor de la insulina.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Endocrinología Molecular La Endocrinología Molecular
Sus antecedentes:
- La señalización del receptor de insulina (IR) regula los procesos celulares clave como el metabolismo y el crecimiento.
- La resistencia a la insulina está relacionada con la diabetes tipo 2 y la enfermedad de Alzheimer.
- La señalización IR aberrante está implicada en varios tipos de cáncer, a menudo interactuando con IGF1R.
Objetivo del estudio:
- Para dilucidar la estructura tridimensional del complejo receptor de insulina-insulina.
- Comprender el mecanismo molecular de la unión de la insulina con el receptor de insulina.
- Proporcionar ideas para el diseño de análogos de insulina terapéutica mejorados.
Principales métodos:
- Cristalografía de rayos X de la insulina unida a las construcciones truncadas de los receptores de insulina.
- Experimentos de Photo-crosslinking para estudiar las interacciones de los holoreceptores.
- Calorimetría de titulación isotérmica para analizar la interfaz de unión.
Principales resultados:
- La interacción primaria de la insulina con el receptor de insulina involucra el segmento carboxiterminal de la cadena α (αCT), no directamente con el dominio L1.
- La unión a la insulina induce un cambio de conformación en el segmento αCT.
- Los residuos específicos de la cadena B de la insulina median el contacto con el receptor.
- Se identificó un nuevo mecanismo de reconocimiento de receptores hormonales dentro de las receptoras tirosina quinasas.
Conclusiones:
- El estudio revela la base estructural del reconocimiento del receptor de insulina-insulina.
- Los hallazgos explican los datos bioquímicos anteriores sobre los receptores de insulina y los sistemas IGF1R.
- Los conocimientos estructurales pueden guiar el desarrollo de nuevas terapias basadas en insulina.
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