Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation
- 1University of Texas Southwestern Medical Center
Abstract
Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.
Related
- Hairpin Architecture and Extended Sequence Context Shape APOBEC3 Mutagenesis in Monkeypox Virus at Different Genomic Scales
- G4SCOPE identifies sequence features and epigenetic contexts of chromatin G-quadruplexes
- Comparative evolutionary pharmacogenomics of human prostaglandin-endoperoxide synthase paralogs identifies population-structured coding variation and protein-contextual candidates in N-terminal leader-sequence and catalytic-channel regions
- Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration
- FastaLake selects compact metaproteomic databases from large sequence reservoirs by de novo peptide lookup
BibTeX
@misc{dashnaw2026largescale,
title = {{Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation}},
author = {C. M. Dashnaw and S. Rastogi and L. A. Joachimiak and I. Memon and K. Jaczynska and B. A. Nguyen and L. Saelices and C. L. A. White and S. Shahmoradian},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757173},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757173v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation
AU - C. M. Dashnaw
AU - S. Rastogi
AU - L. A. Joachimiak
AU - I. Memon
AU - K. Jaczynska
AU - B. A. Nguyen
AU - L. Saelices
AU - C. L. A. White
AU - S. Shahmoradian
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757173
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757173v1
AB - Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.
ER -