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Dinámica de entrada modulada por sustrato en un homólogo transportador de neurotransmisores acoplados con Na+
Yongfang Zhao1, Daniel S Terry, Lei Shi
1Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA.
Nature
|April 26, 2011
Resumen
Los simportores de neurotransmisores utilizan un gradiente Na(+) para recapturar los neurotransmisores. La unión del sustrato en un sitio extracelular controla la apertura de la puerta intracelular, mejorando la eficiencia del transporte y revelando los mecanismos de transporte NSS ocultos.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Los simportadores de neurotransmisores (NSS) terminan la señalización neuronal por la recaptura de los neurotransmisores a través del co-transporte de Na.
- Las SSN clave para la dopamina, la serotonina y la noradrenalina son objetivos para los psicoestimulantes y los antidepresivos.
- La estructura cristalina del homólogo NSS procariótico LeuT reveló conformaciones ocluidas y abiertas hacia el exterior, lo que guió los estudios de mecanismos funcionales.
Objetivo del estudio:
- Investigar cómo la unión de sustrato se acopla a las transiciones estructurales en LeuT durante el transporte acoplado a Na(+).
- Para aclarar el papel de la unión del sustrato extracelular en el control de la dinámica de la puerta intracelular y la eficiencia del transporte.
Principales métodos:
- Utilizamos alanina, un sustrato transportado ~10 veces más rápido que la leucina, para sondear la dinámica del transporte.
- Se observó la dinámica inducida por alanina en la región de la puerta intracelular de LeuT utilizando técnicas avanzadas de imagen.
- Investigó la cooperatividad de unión al sustrato entre los sitios de unión extracelular primarios (S1) y secundarios (S2).
Principales resultados:
- La unión del sustrato en el lado extracelular facilita la apertura de la puerta intracelular y la liberación del sustrato.
- La dinámica inducida por la alanina en la puerta intracelular se correlaciona directamente con la eficiencia del transporte.
- Se identificó la unión de sustratos cooperativos en los sitios S1 y S2 que controlan el gating intracelular durante 30 años.
Conclusiones:
- Reveló aspectos funcionalmente relevantes y previamente ocultos del mecanismo de transporte del NSS.
- Hizo hincapié en el papel crítico de un segundo sustrato (S2) sitio de unión en el vestíbulo extracelular.
- Se ha demostrado que la unión cooperativa controla el encierro intracelular, lo que permite el transporte de Na (((+) impulsado por gradiente.
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