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Las estructuras del dominio alfa L I y su complejo con ICAM-1 revelan una vía de cambio de forma para la regulación
Motomu Shimaoka1, Tsan Xiao1, Jin-Huan Liu2
1The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
Cell
|January 16, 2003
Resumen
La estructura del dominio alfa L beta 2 I de la integrina unida al ICAM-1 revela su conformación abierta. Las señales alostéricas y la unión de ligandos inducen cambios conformacionales, alterando la afinidad de la integrina.
Área de la Ciencia:
- Biología Estructural Biología estructural.
- Inmunología Inmunología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Las integrinas, como la alfa L beta 2, son receptores cruciales de la superficie celular involucrados en la adhesión celular y las respuestas inmunes.
- El dominio I de alfa L beta 2 es crítico para la unión a su ligando, ICAM-1, un miembro de la superfamilia de inmunoglobulinas (IgSF).
- Comprender la base estructural de esta interacción es clave para descifrar el tráfico y la activación de las células inmunes.
Objetivo del estudio:
- Determinar la estructura de alta resolución del dominio de integrina alfa L beta 2 I en complejo con ICAM-1.
- Aclarar los mecanismos estructurales subyacentes a los cambios conformacionales inducidos por ligandos y la modulación de afinidad en las integrinas.
- Para caracterizar la primera interfaz integrina-IgSF en el nivel atómico.
Principales métodos:
- Se utilizó la cristalografía de rayos X para obtener estructuras del dominio alfa L beta 2 I de la integrina.
- Los estudios de mutagenesis se realizaron en variantes de afinidad alta e intermedia.
- Los enlaces de disulfuro fueron diseñados para sondear los estados conformacionales.
Principales resultados:
- La estructura revela la conformación abierta de unión a ligandos del dominio de integrina alfa L beta 2 I unido al ICAM-1.
- Se observó una coordinación directa entre Mg2+ en el dominio I y Glu-34 de ICAM-1, junto con un puente de sal que involucra a Glu-241.
- La unión de ligandos y las señales alostéricas pueden inducir cambios conformacionales de estados cerrados a abiertos, independientemente de la unión de ligandos, modulando la afinidad.
Conclusiones:
- El estudio proporciona la primera visión estructural de un complejo integrina-IgSF, detallando la conformación abierta de unión de ligando.
- La flexibilidad conformal del dominio alfa L I permite la regulación alostérica, permitiendo transiciones entre estados cerrados, intermedios y abiertos.
- Los enlaces de disulfuro diseñados demuestran un mecanismo para ajustar la afinidad de la integrina mediante la estabilización de las conformaciones específicas del bucle.
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