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Cambios conformacionales dependientes de los nucleótidos exportación directa de péptidos por el transportador

James Lee¹, Victor Manon², Jue Chen³

¹Laboratory of Membrane Biophysics and Biology, the Rockefeller University, New York, NY 10065, USA.

|August 30, 2025

Resumen

El transportador asociado con el procesamiento de antígenos (TAP) mueve los péptidos al retículo endoplasmático para las respuestas inmunes. Las estructuras cryo-EM revelan cómo el TAP cambia de forma para transportar y liberar péptidos, evitando el estrés ER.

Área de la Ciencia:

Biología molecular
Inmunología
Biología estructural

Sus antecedentes:

El transportador asociado con el procesamiento de antígenos (TAP) es crucial para la inmunidad adaptativa.
TAP facilita el transporte de péptidos antigénicos desde el citoplasma hasta el retículo endoplasmático (ER).
Este proceso es esencial para la carga de péptidos en las moléculas principales del complejo de histocompatibilidad clase I (MHC-I).

Objetivo del estudio:

Elucidar los mecanismos estructurales de transporte y liberación de péptidos por el heterodímero TAP humano.
Comprender los estados funcionales de TAP a lo largo de su ciclo de transporte.
Para proporcionar una base estructural para fenómenos como el atrapamiento de vanadato y la transinhibición.

Principales métodos:

Se utilizó la crio-microscopía electrónica (crio-EM) para determinar las estructuras de alta resolución.
Las estructuras del heterodímero TAP humano fueron capturadas en múltiples estados funcionales.
El análisis se centró en los cambios conformacionales relacionados con la unión y la hidrólisis de ATP.

Principales resultados:

Se resolvieron distintas conformaciones de TAP orientadas hacia adentro y hacia afuera.
La unión de ATP estabiliza el estado orientado hacia adentro, exponiendo la cavidad del péptido al citosol.
La transición al estado orientado hacia el exterior reconfigura el sitio de unión al péptido para la liberación luminal de ER.
La hidrólisis de ATP y la separación del dominio de unión de nucleótidos impulsan el ciclo de transporte y restablecen el transportador.

Conclusiones:

Se ha establecido un marco estructural completo para el transporte de péptidos mediado por TAP.
Los hallazgos explican el mecanismo de transporte y liberación unilateral de péptidos.
El estudio pone de relieve la base estructural de la transinhibición, un mecanismo de retroalimentación que previene el estrés ER.

Palabras clave:

El transportador ABC Se incluyen los siguientes:inmunidad adaptativa Presentación del antígeno Dominio de unión de nucleótidos transportador asociado con el procesamiento de antígenos

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