title: Signature of an aggregation-prone conformation of tau.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Eschmann
authors.affiliation: National Biomedical Center for Advanced ESR Technology, Cornell University, Ithaca, New York, 14853, USA.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
authors.forename: Elka R
authors.initials: ER
authors.lastname: Georgieva
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Pritam
authors.initials: P
authors.lastname: Ganguly
authors.affiliation: National Biomedical Center for Advanced ESR Technology, Cornell University, Ithaca, New York, 14853, USA.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Borbat
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Maxime D
authors.initials: MD
authors.lastname: Rappaport
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Yasar
authors.initials: Y
authors.lastname: Akdogan
authors.affiliation: National Biomedical Center for Advanced ESR Technology, Cornell University, Ithaca, New York, 14853, USA.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Freed
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, 93106, USA.
authors.forename: Songi
authors.initials: S
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D004583:Electrons; D006493:Heparin / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D066329:Protein Aggregates; D011487:Protein Conformation; D012996:Solutions; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D050505:Mutant Proteins; D010455:Peptides; D066329:Protein Aggregates; D012996:Solutions; D016875:tau Proteins; D006493:Heparin