Signature of an aggregation-prone conformation of tau.
Sci Rep
; 7: 44739, 2017 03 17.
Article
em En
| MEDLINE
| ID: mdl-28303942
ABSTRACT
The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6(*) regions dramatically extend to distances commensurate with extended ß-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended ß-strand conformational state of PHF6(*) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Agregados Proteicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article