ja6b09619_si_002.mpg (4.01 MB)
A Two-Component Adhesive: Tau Fibrils Arise from a Combination of a Well-Defined Motif and Conformationally Flexible Interactions
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posted on 2017-01-26, 00:00 authored by Shengqi Xiang, Natalia Kulminskaya, Birgit Habenstein, Jacek Biernat, Katharina Tepper, Maria Paulat, Christian Griesinger, Stefan Becker, Adam Lange, Eckhard Mandelkow, Rasmus LinserFibrillar
aggregates of Aβ and Tau in the brain are the major
hallmarks of Alzheimer’s disease. Most Tau fibers have a twisted
appearance, but the twist can be variable and even absent. This ambiguity,
which has also been associated with different phenotypes of tauopathies,
has led to controversial assumptions about fibril constitution, and
it is unclear to-date what the molecular causes of this polymorphism
are. To tackle this question, we used solid-state NMR strategies providing
assignments of non-seeded three-repeat-domain Tau3RD with
an inherent heterogeneity. This is in contrast to the general approach
to characterize the most homogeneous preparations by construct truncation
or intricate seeding protocols. Here, carbon and nitrogen chemical-shift
conservation between fibrils revealed invariable secondary-structure
properties, however, with inter-monomer interactions variable among
samples. Residues with variable amide shifts are localized mostly
to N- and C-terminal regions within the rigid beta structure in the
repeat region of Tau3RD. By contrast, the hexapeptide motif
in repeat R3, a crucial motif for fibril formation, shows strikingly
low variability of all NMR parameters: Starting as a nucleation site
for monomer–monomer contacts, this six-residue sequence element
also turns into a well-defined structural element upon fibril formation.
Given the absence of external causes in vitro, the
interplay of structurally differently conserved elements in this protein
likely reflects an intrinsic property of Tau fibrils.