Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau

Luca Ferrari, Riccardo Stucchi, Katerina Konstantoulea, Gerarda Kamp, Renate Kos, Willie J. C. Geerts, Laura S. Bezouwen, Friedrich G. Förster, Maarten Altelaar, Casper C. Hoogenraad and Stefan G. D. Rüdiger ()
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Luca Ferrari: Utrecht University
Riccardo Stucchi: Utrecht University
Katerina Konstantoulea: Utrecht University
Gerarda Kamp: Utrecht University
Renate Kos: Utrecht University
Willie J. C. Geerts: Utrecht University
Laura S. Bezouwen: Utrecht University
Friedrich G. Förster: Utrecht University
Maarten Altelaar: Utrecht University
Casper C. Hoogenraad: Utrecht University
Stefan G. D. Rüdiger: Utrecht University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13745-7

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