Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau

Abstract

Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized. Methods: In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau4RD, the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau4RD/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, α-synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau4RD and of α-synuclein. Conclusions: This study describes the reciprocal influence that Tau4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly.

The Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States

“…The role(s) of anions in tau self-assembly have remained elusive. Many pioneering manuscripts have shown that individual polyanions promote this process 22,27,33,47,48 , with the most attention placed on heparins and polyphosphates. Here, we expand the landscape of tested anions, with a special focus on those naturally occurring ones that tau might encounter in the brain.…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…Lipid membranes promoted Tau self-assembly at the membrane surface. 145,451 MTBR was identified as a lipid-binding domain, 452,453 with interactions specifically mediated by the PHF6 region. 454 Lipid membranes were found to induce a shift in full-length Tau molecular conformation towards b-sheet-containing structures, that formed stable oligomeric complexes.…”

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

“…Interaction with phospholipids or free fatty acids can also induce the aggregation of full-length tau (62, 130) or a tau fragment comprising the MBR (131). Interestingly, it has also been reported that the NTR can contribute to tau polymerization because a disease-associated R5L mutation in the NTR increases tau polymerization (132).…”