Abstract
Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils.
Highlights
Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease
We tracked interactome changes associated to the formation of Tau fibrils, a hallmark of Alzheimer’s disease
As Tau fibrils form, they attract abnormal interactors endowed with long disordered stretches with specific amino acidic bias
Summary
Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease. Protein aggregation proceeds in a step-wise fashion, from structurally heterogenous oligomeric species to mature fibrils, the former considered to be the most toxic agents[4,5]. Non-physiological protein aggregates may result in new interactions within the cell, disturbing a variety of cellular processes and disrupting the protein quality control network, responsible for fibrils handling and disposal[12,13] Major components of this network are two conserved energy-driven chaperone systems, Hsp[70] and Hsp9014. We recently showed that toxicity of an aggregation-prone variant of the protein Axin is caused by aberrant interactions established by oligomeric nano-aggregates formed in the cytoplasm[23] Together, this made us wonder how Tau fibrils would interact with the soluble cytoplasmic component of the brain, where protein aggregation takes place. It is of great interest to understand which interactions are engaged by Tau fibrils and their binding mechanisms, as this would reveal which cellular processes are targeted by Taudependent neurodegeneration and would offer novel therapeutic strategies
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