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Bases estructurales para la proteólisis regulada por la α-secretasa ADAM10

Tom C M Seegar¹, Lauren B Killingsworth¹, Nayanendu Saha²

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

|December 12, 2017

Resumen

Los investigadores descubrieron la estructura de ADAM10, una enzima crucial para la señalización celular y la enfermedad de Alzheimer. Descubrieron que su actividad está regulada por su propia estructura, ofreciendo nuevas formas de controlar esta enzima importante.

Área de la Ciencia:

La bioquímica
Biología estructural
Biología celular

Sus antecedentes:

Las endopeptidasas ADAM (una desintegrina y metaloproteinasa) son vitales para la transducción de señales y la rotación de proteínas.
ADAM10 divide específicamente los receptores de Notch y la proteína precursora del Alzheimer (APP).

Objetivo del estudio:

Para aclarar la estructura cristalina de rayos X del ectodominio ADAM10.
Comprender los mecanismos regulatorios que rigen la actividad de ADAM10.

Principales métodos:

Cristalografía de rayos X del ectodominio ADAM10.
Pruebas bioquímicas.
Estudios de las células.

Principales resultados:

El ectodominio ADAM10 exhibe una arquitectura autoinhibidora donde el dominio rico en cisteína bloquea parcialmente el sitio activo.
La unión de un anticuerpo específico al dominio rico en cisteína alivia esta autoinhibición, aumentando la actividad enzimática.
Esto revela un nuevo mecanismo de regulación para la actividad de ADAM10.

Conclusiones:

La actividad de ADAM10 está regulada intrínsecamente por su organización de dominio.
La modulación de ADAM10 a través de la unión de anticuerpos proporciona una estrategia terapéutica potencial.
La comprensión de este reglamento ofrece una hoja de ruta para el desarrollo de moduladores ADAM10.

Palabras clave:

ADAM10 (en inglés)Señales de muesca Cristalografía de rayos X Proteínas precursoras de las amiloides

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