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Conocimientos estructurales sobre el voltaje y la activación fosfolípida del canal TPC1 de los mamíferos
Ji She1,2, Jiangtao Guo3, Qingfeng Chen1,2,4
1Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
Nature
|March 22, 2018
Resumen
Las ideas estructurales en el ratón TPC1 (MmTPC1) revelan cómo se abre este canal de sodio dependiente de la tensión. La unión al fosfatidilinositol 3,5-bisfosfato (PtdIns(3,5) P2 y la despolarización de la membrana regulan el encierro de MmTPC1 y la selectividad iónica.
Área de la Ciencia:
- Biología estructural
- Biofísica de los canales iónicos
- Fisiología celular
Sus antecedentes:
- Los canales orgánicos de dos poros (TPC) son canales iónicos controlados por voltaje que son cruciales para la función endolisosómica.
- Los TPC1 y TPC2 de los mamíferos están localizados en las membranas endolisomales, regulando la fisiología de los orgánulos.
- Las TPC son homodímeros, cada subunidad contiene seis dominios de transmembrana (6-TM).
Objetivo del estudio:
- Aclarar los mecanismos estructurales subyacentes a la función y la regulación de la TPC1 de los mamíferos.
- Proporcionar información sobre la selectividad iónica y los mecanismos de bloqueo de los canales TPC.
- Para entender la interacción entre el voltaje y la activación del ligando lipídico.
Principales métodos:
- Crio-microscopía electrónica (crio-EM) para determinar las estructuras del TPC1 del ratón (MmTPC1).
- Análisis funcional para validar los hallazgos estructurales y comprender la apertura de canales.
- Comparaciones estructurales de estados abiertos y cerrados por ligando.
Principales resultados:
- Determinación de las estructuras cryo-EM de alta resolución de MmTPC1 en estados abiertos apo cerrados y PtdIns ((3,5) P2-ligados.
- Se identificó una vía iónica en forma de ranura de moneda responsable de la selectividad del Na+.
- Se reveló que solo el segundo dominio 6-TM confiere dependencia de voltaje.
- La unión de PtdIns ((3,5) P2 al primer dominio 6-TM activa el canal al despolarizarse.
Conclusiones:
- Las estructuras de MmTPC1 proporcionan una visión completa de la selectividad y el control de los canales TPC de los mamíferos.
- El estudio pone de relieve el papel del dominio de detección de tensión en la dependencia de tensión.
- Demuestra la activación mediada por PtdIns ((3,5) P2 y la interacción del voltaje y la regulación lipídica.
- Revela nuevos aspectos de la unión y regulación de lípidos en los canales de voltaje 6-TM.
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