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Los monómeros del polipéptido amiloide de las islas humanas forman beta-hairpins ordenados: un posible precursor

Nicholas F Dupuis¹, Chun Wu, Joan-Emma Shea

¹Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, USA.

Journal of the American Chemical Society

|December 3, 2009

Resumen

El monómero del polipéptido amiloide de islotes humanos (IAPP) adopta estructuras de horquilla beta, identificadas a través de la espectrometría de masas de movilidad iónica y simulaciones de dinámica molecular. Estas estructuras son cruciales para la fibrilación IAPP en la diabetes tipo II.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
La biofísica molecular es la biofísica molecular.

Sus antecedentes:

La oligomerización del polipéptido amiloide de islotes humanos (IAPP) está implicada en la patogénesis de la diabetes tipo II.
Comprender la estructura monomérica de la IAPP es clave para elucidar su vía de fibrilación.

Objetivo del estudio:

Para investigar las características estructurales del monómero IAPP humano.
Para identificar distintas familias conformacionales de monómero IAPP en solución.
Para explorar el papel de las conformaciones específicas en la fibrilación IAPP.

Principales métodos:

Espectrometría de masas de movilidad iónica (IMS-MS) para la exploración estructural experimental.
Simulaciones de dinámica molecular (REMD) de intercambio de réplica de todos los átomos para el análisis computacional.
Estudios comparativos con ratas no amiloidogénicas IAPP y estudios de dependencia del pH.

Principales resultados:

Se observaron experimentalmente tres familias conformacionales distintas de monómero IAPP humano.
Se identificaron dos familias como estructuras de solución deshidratada: una horquilla beta extendida y una bobina helicoidal compacta.
La conformación beta-hairpin, ausente en la IAPP de rata, es topológicamente similar a las estructuras de las fibrillas y su población aumenta a un pH de 8.0.

Conclusiones:

Presenta las primeras pruebas experimentales de una población significativa de conformistas beta-hairpin de IAPP.
Sugiere que las horquillas beta ordenadas, no las estructuras en espiral, pueden ensamblarse en oligómeros ricos en hojas beta.
La conformación beta-hairpin probablemente juega un papel crítico en la vía de fibrilación de la IAPP humana y explica la fibrilación dependiente del pH.

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