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

• Published in: Nature communications Vol. 14; no. 1; pp. 1625 - 17
• Main Authors: Chen, Dailu, Bali, Sofia, Singh, Ruhar, Wosztyl, Aleksandra, Mullapudi, Vishruth, Vaquer-Alicea, Jaime, Jayan, Parvathy, Melhem, Shamiram, Seelaar, Harro, van Swieten, John C., Diamond, Marc I., Joachimiak, Lukasz A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 119/118; 13/31; 631/45/470/460; 631/535/1267; 631/57/2272/2273; 82/83; Agglomeration; Amyloid; Amyloid - genetics; Amyloidogenic Proteins - genetics; Clustering; Dementia disorders; Frontotemporal dementia; Frontotemporal Dementia - genetics; Genetic suppression; Humanities and Social Sciences; Humans; Hydrophobicity; Microbalances; Missense mutation; multidisciplinary; Mutation; Mutation, Missense; Neurodegenerative diseases; Phenotypes; Reagents; Science; Science (multidisciplinary); Tau protein; tau Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37274-6

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 306 VQIVYK 311 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. The authors used multi-disciplinary approaches to understand the structural mechanism underlying spontaneous aggregation of tau encoding an S320F FTD-tau mutant. Understanding the mechanisms of tau aggregation will help identify novel methods to regulate its misfolding.