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

Dailu Chen, Sofia Bali, Ruhar Singh, Aleksandra Wosztyl, Vishruth Mullapudi, Jaime Vaquer-Alicea, Parvathy Jayan, Shamiram Melhem, Harro Seelaar, John C. Swieten, Marc I. Diamond and Lukasz A. Joachimiak ()
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Dailu Chen: University of Texas Southwestern Medical Center
Sofia Bali: University of Texas Southwestern Medical Center
Ruhar Singh: University of Texas Southwestern Medical Center
Aleksandra Wosztyl: University of Texas Southwestern Medical Center
Vishruth Mullapudi: University of Texas Southwestern Medical Center
Jaime Vaquer-Alicea: University of Texas Southwestern Medical Center
Parvathy Jayan: University of Texas Southwestern Medical Center
Shamiram Melhem: Erasmus Medical Center
Harro Seelaar: Erasmus Medical Center
John C. Swieten: Erasmus Medical Center
Marc I. Diamond: University of Texas Southwestern Medical Center
Lukasz A. Joachimiak: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

Date: 2023
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DOI: 10.1038/s41467-023-37274-6

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