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Generating a Fractal Microstructure of Laminin-111 to Signal to Cells
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Se requiere la fosforilación O-mannosil del alfa-distroglicano para la unión a la laminina
Takako Yoshida-Moriguchi1, Liping Yu, Stephanie H Stalnaker
1Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 4283 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242-1101, USA.
Science (New York, N.Y.)
|January 2, 2010
Resumen
Los defectos en una modificación específica del azúcar en el alfa-distroglicano (alfa-DG), mediada por la proteína LARGE, causan distrofias musculares congénitas al deteriorar la unión de la laminina.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- El alfa-distroglicano (alfa-DG) es una glicoproteína crucial de la superficie celular involucrada en las interacciones de la matriz extracelular.
- Su función como receptor de la laminina es esencial para la integridad muscular.
- Los defectos en la glicosilación alfa-DG están relacionados con las distrofias musculares congénitas.
Objetivo del estudio:
- Para aclarar la base estructural de la unión de la laminina a la alfa-DG.
- Para identificar los defectos moleculares subyacentes a las distrofias musculares congénitas específicas.
- Para investigar el papel de la proteína LARGE en la modificación alfa-DG.
Principales métodos:
- Espectrometría de masas y resonancia magnética nuclear (RMN) para el análisis estructural.
- Pruebas bioquímicas para evaluar la unión a las proteínas.
- Análisis de muestras de pacientes y modelos animales.
Principales resultados:
- Se identificó un glicano O-mannosil fosforilado en el dominio mucino-como de alfa-DG como esencial para la unión de la laminina.
- Los pacientes con enfermedad músculo-ojo-cerebro y distrofia muscular congénita de Fukuyama, y los ratones miodistróficos, exhiben defectos en una modificación postfosforil de este glicano.
- La proteína LARGE fue identificada como el mediador clave de esta crítica modificación postfosforila.
Conclusiones:
- El estudio revela un defecto específico de glicosilación en alfa-DG como causa de las distrofias musculares congénitas.
- El papel de la proteína LARGE en la modificación de los O-mannosyl glicanos es crítico para la función alfa-DG y la prevención de la distrofia muscular.
- Estos hallazgos proporcionan nuevos conocimientos sobre la patogénesis de las distrofias musculares congénitas y posibles objetivos terapéuticos.
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