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

Nat Commun. 2020 Jan 29;11(1):571. doi: 10.1038/s41467-019-13745-7.

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.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyloid / metabolism*
  • Animals
  • Arginine / chemistry
  • Arginine / metabolism*
  • Disease Progression
  • Guanidine / metabolism
  • HSP90 Heat-Shock Proteins
  • Humans
  • Mass Spectrometry
  • Molecular Chaperones
  • Protein Aggregates
  • Protein Binding*
  • Protein Domains
  • Protein Folding
  • Proteome
  • Rats
  • Sequence Analysis, Protein
  • tau Proteins / chemistry
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Amyloid
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Protein Aggregates
  • Proteome
  • tau Proteins
  • Arginine
  • Guanidine