Single mutations in tau modulate the populations of fibril conformers through seed selection

Virginia Meyer, Paul D. Dinkel, Yin Luo, Xiang Yu, Guanghong Wei, Jie Zheng, Gareth R. Eaton, Buyong Ma, Ruth Nussinov, Sandra S. Eaton, Martin Margittai

Research output: Contribution to journalArticlepeer-review

Abstract

Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer's disease and other neurodegenerative disorders. Self-assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron-electron resonance spectroscopy was used to investigate the conformational ensemble of four-repeat tau fibrils. Single point mutations at key positions in the protein (ΔK280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template-assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation. It takes only one mutation: The conformational ensembles of four-repeat tau fibrils, formed after templated growth, have been determined by double electron-electron resonance spectroscopy through the measurement of distances between two spin labels. The results indicate that single mutations in tau can alter the populations of fibril conformers based on the selection of structurally compatible seeds.

Original languageEnglish
Pages (from-to)1590-1593
Number of pages4
JournalAngewandte Chemie - International Edition
Volume53
Issue number6
DOIs
StatePublished - 3 Feb 2014

Keywords

  • Alzheimer's disease
  • EPR spectroscopy
  • conformation analysis
  • proteins
  • tau fibrils

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