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Millisecond Hydrogen/Deuterium-Exchange Mass Spectrometry for the Study of Alpha-Synuclein Structural Dynamics Under Physiological Conditions
Published on: June 23, 2022
Allosterio en una proteína desordenada: las modificaciones oxidativas de la α-sinucleína actúan distalmente para
Eva Sevcsik1, Adam J Trexler, Joanna M Dunn
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA.
Journal of the American Chemical Society
|April 16, 2011
Resumen
La nitratación oxidativa de la alfa-sinucleína (aS) interrumpe su unión crucial a la membrana. Esto ocurre incluso cuando la nitratación está en la región C-terminal, lo que sugiere una regulación alostérica en la patogénesis de la enfermedad de Parkinson.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
Sus antecedentes:
- El estrés oxidativo y la agregación de alfa-sinucleína (aS) son claves en la enfermedad de Parkinson.
- Las modificaciones oxidativas de aS perjudican su unión a la membrana lipídica esencial.
- Comprender estas modificaciones es crucial para los mecanismos de la enfermedad de Parkinson.
Objetivo del estudio:
- Explicar de manera mecanicista cómo la nitratación oxidativa afecta a la estructura de AS y la interacción de la membrana.
- Para investigar el impacto de la nitratación de residuos de tirosina en la unión lipídica aS.
- Para explorar el papel de la regulación alostérica en la función AS.
Principales métodos:
- Investigó los efectos de la nitratación de tirosina en la estructura AS y la interacción de la membrana lipídica.
- Cambios analizados en los estados conformacionales aS en solución.
- Se examinó el impacto de la nitratación en la afinidad de unión a la membrana.
Principales resultados:
- La nitratación de la tirosina Y39 en el dominio N-terminal interrumpe la unión de la membrana a través de la repulsión electrostática.
- La nitratación de las tirosinas C-terminales (Y125/133/136) también perturba la unión, contrariamente a las expectativas.
- La nitratación de tirosina altera los estados conformacionales de AS, particularmente en el extremo C, lo que sugiere una regulación alostérica.
Conclusiones:
- La nitratación de tirosina, especialmente en el extremo C, reduce la afinidad de unión a la membrana aS a través del acoplamiento alostérico.
- La regulación alostérica a través de modificaciones en la terminación C puede ser un mecanismo general para modular la función AS.
- Este estudio proporciona información sobre la patogénesis de la enfermedad de Parkinson y posibles objetivos terapéuticos.
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