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Estructura de una esterol reductasa de membrana integral obtenida de Methylomicrobium alcaliphilum

Xiaochun Li¹, Rita Roberti², Günter Blobel¹

¹Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.

|October 14, 2014

Resumen

Determinamos la estructura cristalina de una Δ(14)-sterol reductasa bacteriana (MaSR1), revelando su estructura y mecanismo de membrana integral. Esto proporciona información molecular sobre las esteroles reductasas humanas vinculadas a enfermedades congénitas.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
Biología Molecular Biología Molecular

Sus antecedentes:

Los esteroles son moléculas vitales para la vida, sintetizadas a través de vías complejas que involucran a las esteroles reductasas.
Las principales esteroles reductasas incluyen la Δ(14)-esterol reductasa (C14SR), la 7-dehidrocolesterol reductasa (DHCR7) y la 24-dehidrocolesterol reductasa (DHCR24).
El receptor Lamin B (LBR) también posee un dominio C14SR, destacando la importancia de esta familia de enzimas.

Objetivo del estudio:

Para dilucidar la estructura y el mecanismo de las esteroles reductasas de membrana integral.
Proporcionar información molecular sobre las enfermedades humanas causadas por mutaciones en DHCR7 y LBR.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar la estructura de MaSR1 de Methylomicrobium alcaliphilum 20Z con NADPH.
Se realizó una comparación bioinformática con el esteroide soluble 5β-reductasa.
Se realizaron ensayos de actividad de la esterol reductasa.

Principales resultados:

Se determinó la estructura cristalina de MaSR1, un homólogo del C14SR humano, DHCR7 y LBR.
MaSR1 presenta diez segmentos transmembranares y un dominio catalítico con dos bolsillos interconectados, uno citoplasmático y otro accesible a los lípidos.
La estructura sugiere que el NADPH y el sustrato de esteroles interactúan en la unión del bolsillo.
MaSR1 demostró actividad de la reductasa en un intermediario biosintético del colesterol, confirmando la conservación funcional.

Conclusiones:

La estructura de MaSR1 sirve como prototipo para las esteroles reductasas de membrana integral.
Esta información estructural ofrece información molecular sobre los mecanismos subyacentes a las enfermedades humanas relacionadas con las mutaciones DHCR7 y LBR.
Comprender estas enzimas es crucial para descifrar la biosíntesis de esteroles y las patologías relacionadas.

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