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Title: Signature of an aggregation-prone conformation of tau
Authors: Eschmann, Neil A.
Georgieva, Elka R.
Ganguly, Pritam
Borbat, Peter P.
Rappaport, Maxime D.
Akdoğan, Yaşar
Freed, Jack H.
Shea, Joan-Emma
Han, Songi
Keywords: Tau protein
Intrinsically disordered protein
Neurofibrillary tangles
Publisher: Nature Publishing Group
Source: Eschmann, N. A., Georgieva, E. R., Ganguly, P., Borbat, P. P., Rappaport, M. D., Akdoğan, Y., Freed, J. H., Shea, J.-E., and Han, S. (2017). Signature of an aggregation-prone conformation of tau. Scientific Reports, 7. doi:10.1038/srep44739
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 β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-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.
ISSN: 2045-2322
Appears in Collections:Materials Science and Engineering / Malzeme Bilimi ve Mühendisliği
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection

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