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Bases estructurales de la subversión lentiviral de una vía de degradación de proteínas celulares

David Schwefel¹, Harriet C T Groom², Virginie C Boucherit²

¹Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

|December 17, 2013

Resumen

Las proteínas accesorias lentivirales como Vpx secuestran la maquinaria celular para degradar SAMHD1, una proteína de defensa del huésped que bloquea la infección por el VIH-1. Este estudio estructural revela cómo Vpx se dirige a SAMHD1 para la destrucción, superando la restricción viral.

Área de la Ciencia:

Virología Virología.
Biología Estructural Biología estructural.
Mecanismos moleculares de las moléculas.

Sus antecedentes:

Los lentivirus poseen genes accesorios para superar las defensas del huésped.
SAMHD1 es un factor de restricción que inhibe el VIH-1 y otros lentivirus mediante el agotamiento de los trifosfatos desoxinucleósidos.
Las proteínas virales Vpx / Vpr del VIH-2 / SIV contrarrestan SAMHD1 al dirigirse a la degradación proteasoma.

Objetivo del estudio:

Para aclarar el mecanismo molecular por el cual la proteína Vpx lentiviral se dirige a SAMHD1 para la degradación.
Determinar la base estructural del reclutamiento mediado por Vpx de SAMHD1 al complejo de E3 ligasa.

Principales métodos:

Cristalografía de rayos X de un complejo ternario.
Análisis estructural de Vpx, DCAF1 y SAMHD1 región C-terminal.

Principales resultados:

Se determinó la estructura cristalina del complejo Vpx-DCAF1-SAMHD1.
Vpx forma un haz de tres hélices con un motivo de dedo de zinc, uniendo DCAF1 y presentando una nueva superficie.
Esta superficie recluta el extremo C de SAMHD1, lo que lo marca para la degradación proteasomal mediada por la ligasa E3.

Conclusiones:

El estudio proporciona una comprensión molecular de cómo las proteínas accesorias lentivirales subvierten las vías de degradación de las proteínas del huésped.
Vpx utiliza la adaptación estructural para reclutar SAMHD1, inactivando así un mecanismo de defensa celular clave contra la infección lentiviral.

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