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

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

SUBMITTER: Chen D 

PROVIDER: S-EPMC10036635 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature