FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Amyloid deposition of microtubule-associated protein tau is linked to neurodegenerative diseases.
• Missense mutations in tau, observed in frontotemporal dementia with abnormal tau (FTD-tau), increase its aggregation propensity.

Purpose of the Study:

• To elucidate the structural mechanism by which the FTD-tau S320F mutation promotes spontaneous tau aggregation.
• To identify strategies for controlling tau aggregation pathways.

Main Methods:

• Integration of in vitro, in silico (computational), and cellular experiments.
• Structural analysis of tau mutations and their effects on aggregation motifs.
• Computational engineering of tau sequences to optimize aggregation propensity.

Main Results:

• The S320F mutation stabilizes a local hydrophobic cluster, allosterically exposing the ³⁰⁶VQIVYK³¹¹ amyloid motif.
• A suppressor mutation was identified that destabilizes S320F-induced hydrophobic clustering, reversing the aggregation phenotype.
• Computationally engineered tau sequences demonstrated optimized nonpolar clusters around S320, leading to spontaneous aggregation.

Conclusions:

• A regulatory mechanism for tau aggregation involves balancing local nonpolar contacts with long-range interactions that sequester amyloid motifs.
• Understanding this mechanism could enable the design of reagents targeting disease-specific tau conformations for therapeutic intervention.