Format

Send to

Choose Destination
Nat Commun. 2019 Jun 7;10(1):2493. doi: 10.1038/s41467-019-10355-1.

Tau local structure shields an amyloid-forming motif and controls aggregation propensity.

Author information

1
Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
2
Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
3
Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
4
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
5
Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Lukasz.Joachimiak@utsouthwestern.edu.
6
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Lukasz.Joachimiak@utsouthwestern.edu.

Abstract

Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau's repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone 306VQIVYK311 motif forms metastable compact structures with its upstream sequence that modulates aggregation propensity. We report that disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.

PMID:
31175300
PMCID:
PMC6555816
DOI:
10.1038/s41467-019-10355-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center