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Updated: May 3, 2026
In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening
Published on: November 20, 2018
The influence of the ΔK280 mutation and N- or C-terminal extensions on the structure, dynamics, and fibril morphology
Yoav Raz1, Juliane Adler, Alexander Vogel
1Department of Chemistry, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel. ymiller@bgu.ac.il.
Abstract:
Tau is a microtubule-associated protein and is involved in microtubule assembly and stabilization. It consists of four repeats that bind to the microtubule. The ΔK280 deletion mutation in the tau R2 repeat region is directly associated with the development of the frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17). This deletion mutation is known to accelerate tau R2 repeat aggregation. However, the secondary and the tertiary structures of the self-assembled ΔK280 tau R2 repeat mutant aggregates are still controversial. Moreover, it is unclear whether extensions by one residue in the N- or the C-terminus of this mutant can influence the secondary or the tertiary structure. Herein, we combine solid-state NMR, atomic force microscopy, electron microscopy and all-atom explicit molecular dynamics simulations to investigate the effects of the deletion mutation and the N- and the C-terminal extension of this mutant on the structure. Our main findings show that the deletion mutation induces the formation of small aggregates, such as oligomers, and reduces the formation of fibrils. However, the extensions in the N- or the C-terminus revealed more fibril formation than small aggregates. Further, in the deletion mutation only one structure is preferred, while the N- and the C-terminal extensions strongly lead to polymorphic states. Finally, our broad and combined experimental and computational techniques provide direct structural information regarding ΔK280 tau R2 repeat mutant aggregates and their extensions in the N- and C-terminii by one residue.
Insights
The ΔK280 tau mutation forms small aggregates, but N- or C-terminal extensions promote fibril formation. These extensions also lead to diverse aggregate structures, unlike the single structure formed by the deletion mutation alone.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Tau protein stabilizes microtubules; mutations like ΔK280 in its R2 repeat are linked to frontotemporal dementia parkinsonism (FTDP-17).
- The aggregation of the ΔK280 tau mutant is known, but its structural details remain debated.
Purpose of the Study:
- To investigate the structural impact of the ΔK280 deletion mutation in tau R2 repeat aggregates.
- To determine how single-residue N- or C-terminal extensions affect the structure of ΔK280 tau R2 repeat aggregates.
Main Methods:
- Solid-state Nuclear Magnetic Resonance (NMR)
- Atomic Force Microscopy (AFM)
- Electron Microscopy (EM)
- All-atom explicit molecular dynamics simulations
Main Results:
- The ΔK280 deletion mutation favors small aggregates (oligomers) over fibrils.
- N- and C-terminal extensions of the ΔK280 mutant promote fibril formation.
- The deletion mutation results in a single preferred aggregate structure, while extensions lead to polymorphic states.
Conclusions:
- Combined experimental and computational methods elucidate the structural consequences of the ΔK280 tau mutation and its extensions.
- N- and C-terminal extensions significantly alter the aggregation pathway and structural diversity of tau mutants associated with neurodegenerative diseases.
