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Estructura y mecanismo catalítico de la histona humana metiltransferasa SET7/9

Bing Xiao¹, Chun Jing, Jonathan R Wilson

¹Structural Biology Group, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.

|January 24, 2003

Resumen

La SET7/9 humana es una mono-metilasa única, a diferencia de otras proteínas SET. Su estructura cristalina revela cómo se unen las histonas diana y los cofactores, lo que explica la especificidad de la metilación y los mecanismos de reacción.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
La epigenética es la epigenética.

Sus antecedentes:

Las modificaciones post-traduccionales de la histona, incluida la acetilación, la fosforilación y la metilación, regulan la estructura y la función de la cromatina.
La metilación de la histona es catalizada principalmente por las enzimas del dominio SET (Su(var) 3-9, Enhancer-of-zeste, Trithorax, con la mayoría de las enzimas conocidas que metilan residuos específicos de lisina.

Objetivo del estudio:

Para aclarar la base estructural de la especificidad de la metilación de histonas por SET7 / 9.9 humano.
Comprender el mecanismo de la metilación mediada por SET7/9 y su interacción con el cofactor.
Para caracterizar SET7/9 como una mono-metilasa.

Principales métodos:

Determinación de la estructura cristalina de alta resolución de un complejo ternario que involucra al SET7 / 9 humano, un péptido de histona y el cofactor S-adenosil-l-metionina (AdoMet).
Estudios de soluciones para confirmar la actividad enzimática y la especificidad del sustrato.
Análisis estructural para identificar las principales interacciones y canales dentro del sitio activo de la enzima.

Principales resultados:

La estructura cristalina revela que el sustrato del péptido histona y el cofactor AdoMet se unen a las superficies opuestas de SET7/9.9.
Un canal estrecho dentro de la enzima facilita el acceso de la cadena lateral de lisina objetivo al sitio activo y al cofactor.
Se confirmó que SET7/9 es exclusivamente una mono-metilasa, lo que lo distingue de otras proteínas SET.
La estructura proporciona información sobre la base molecular de la especificidad de SET7/9 hacia su histona diana.

Conclusiones:

La estructura del complejo SET7/9-péptido histona-AdoMet revela un modo de unión y un canal únicos para el acceso al sustrato.
SET7/9 funciona como una mono-metilasa específica, con sus características estructurales que explican el reconocimiento del sustrato y el mecanismo de reacción.
Los hallazgos contribuyen a comprender las diversas funciones de las proteínas del dominio SET en la regulación epigenética.

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