(308g) Interaction of Tau Protein with Model Lipid Membranes Induces Tau Structural Compaction | AIChE

(308g) Interaction of Tau Protein with Model Lipid Membranes Induces Tau Structural Compaction


Chi, E. Y., University of New Mexico
Camp, P. J., University of New Mexico
Vernon, B. C., University of New Mexico
Biernat, J., Max Planck Unit for Structural Biology
Mandelkow, E., Max Planck Unit for Structural Biology
Majewski, J., Los Alamos National Laboratory
Dubey, M., University of Washington
Singh, S., Los Alamos Neutron Science Center, Los Alamos National Laboratory
Junghans, A., Los Alamos Neutron Science Center, Los Alamos National Laboratory

The misfolding and aggregation of proteins into b-sheet rich fibrillar
aggregates in vivo are linked to the
pathogenesis of over twenty neurodegenerative diseases, including Alzheimer's disease.
Alzheimer's disease is a progressive neurodegenerative disease characterized in
part by neurofibrillary tangles (NFTs) found in the
brains of affected patients.  NFTs are
composed of misfolded aggregates of the intrinsically
disordered microtubule associated protein tau. In order to aggregate into
fibrils, the intrinsically disordered, highly soluble, and highly stable tau
needs to undergo conformational changes that render the protein
aggregation-competent or ?pro-aggregant?.  The ?pro-aggregant?
form is currently unknown, but the formation of β-sheet enriched fibrils
from tau likely proceeds through the formation of partially folded, or
structurally compact, conformations with increased aggregation propensities. In vitro, aggregation can be induced by polyanionic cofactors such as heparin and anionic micelles
or vesicles, which compensate for tau's positive
charges.  This suggests that aggregation
proceeds through a nucleation controlled polymerization pathway, but the molecular basis of the early
aggregation events, such as the structural fluctuations that trigger the
aberrant accumulation of tau into NFTs rich in β-sheets in vivo, remains unknown.This prompted our investigation
to assess tau's propensity to interact with membranes and to elucidate the structural perturbations those
interactions induce in the tau protein. We show that although highly charged
and soluble, tau is also highly surface active. 
Tau strongly interacts with anionic membranes and does not exhibit any
favorable interaction with neutrally charged membranes.  To resolve molecular-scale structural details
of protein associated with anionic lipid membranes, we utilized X-ray
scattering techniques. X-ray reflectivity indicated tau's
presence underneath an anionic DMPG monolayer at the air/water interface and
penetration into the lipid headgroups and tailgroups. More significantly, both air/water and DMPG
lipid membrane interfaces induce the disordered, molten globule-like, tau to
partially adopt a more compact conformation with a density similar to that of a
folded protein. To investigate the effect of tau-membrane interactions on tau
fibril formation, we also incubate the protein with lipid vesicles containing
either neutrally charged or anionic lipids. 
Thioflavin-S binding assay is used to detect
fibril formation and transmission electron microscopy is used to image the
morphology of aggregates formed. Our results show that tau is highly surface
active and strongly interacts with anionic lipid membranes, leading to tau
structural compaction which may render the protein ?pro-aggregant?
or aggregation-competent.  This suggests possible
membrane-based mechanisms of tau aggregation in neurodegenerative diseases.