bi0c00342_si_001.pdf (3.16 MB)
Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance
journal contribution
posted on 2020-06-05, 17:33 authored by Aurelio
J. Dregni, Pu Duan, Mei HongThe
microtubule-associated protein tau aggregates into distinct
neurofibrillary tangles in brains afflicted with multiple neurodegenerative
diseases such as Alzheimer’s disease and corticobasal degeneration
(CBD). The mechanism of tau misfolding and aggregation is poorly understood.
Determining the structure, dynamics, and water accessibility of tau
filaments may provide insight into the pathway of tau misfolding.
Here, we investigate the hydration and dynamics of the β-sheet
core of heparin-fibrillized 0N4R tau using solid-state nuclear magnetic
resonance spectroscopy. This β-sheet core consists of the second
and third microtubule-binding repeats, R2 and R3, respectively, which
form a hairpin. Water-edited two-dimensional (2D) 13C–13C and 15N–13C correlation spectra
show that most residues in R2 and R3 domains have low water accessibility,
indicating that this hairpin is surrounded by other proteinaceous
segments. However, a small number of residues, especially S285 and
S316, are well hydrated compared to other Ser and Thr residues, suggesting
that there is a small water channel in the middle of the hairpin.
To probe whether water accessibility correlates with protein dynamics,
we measured the backbone N–H dipolar couplings of the β-sheet
core. Interestingly, residues in the fourth microtubule-binding repeat,
R4, show rigid-limit N–H dipolar couplings, even though this
domain exhibits weaker intensities in the 2D 15N–13C correlation spectra. These results suggest that the R4
domain participates in cross-β hydrogen bonding in some of the
subunits but exhibits dynamic disorder in other subunits. Taken together,
these hydration and dynamics data indicate that the R2–R3 hairpin
of 0N4R tau is shielded from water by other proteinaceous segments
on the exterior but contains a small water pore in the interior. This
structural topology has various similarities with the CBD tau fibril
structure but also shows specific differences. The disorder of the
R4 domain and the presence of a small water channel in the heparin-fibrillized
4R tau have implications for the structure of tau fibrils in diseased
brains.
History
Usage metrics
Categories
Keywords
dynamicFull-Length Tau Amyloid Fibrils InvestigatedhairpinR 3 domainsproteinaceous segmentsresidueR 2heparin-fibrillized 0 N 4R tauwater accessibilitymicrotubule-associated protein tau aggregateswater accessibility correlateswater channelheparin-fibrillized 4 R tauCBD tau fibril structureR 4 domain0 N 4R tauβ- sheet coretau misfolding
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC