Abstract
Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using this knowledge, we demonstrate, using tau as a model system, that predicted cross-interactions driven by sequence homology indeed can modify nucleation, fibril morphology, kinetic assembly and cellular spreading of aggregates. We also find that these heterotypic amyloid interactions can result in the mis-localisation of brain-expressed protein sequences with prevalent activities in neurodegenerative disorders. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Author names corrected; Acknowledgements updated
Abbreviations
- APRs
- aggregation prone regions
- PCA
- principal component analysis
- UMAP
- uniform manifold approximation and projection
- AD
- alzheimer’s disease
- PD
- parkinson’s Disease
- Aβ
- beta-amyloid peptide
- Apo-AI
- apolipoprotein A-I
- HA-tag
- human influenza hemagglutinin tag
- IRES
- internal ribosome entry site
- PHF
- pair helical fragment
- CFP
- cyan-fluorescent protein
- YFP
- yellow-fluorescent protein
- FRET
- Förster resonance energy transfer
- CBD
- corticobasal degeneration
- CJD
- Creutzfeldt-Jakob disease
- FTD
- frontotemporal dementia
- TEM
- transmission Electron Microscopy
- FTIR
- Fourier-transform infrared spectroscopy
- cryo-EM
- cryogenic electron microscopy
- NMR
- nuclear magnetic resonance
- CMV
- cytomegalovirus
- PVDF
- polyvinylidene fluoride
- FRAP
- fluorescence recovery after photobleaching
- T2D
- type-2 diabetes
- RP-HPLC
- reverse-phase high-performance liquid chromatography
- BSA
- bovine serum albumin
- NHS
- succinimidyl ester
- DOCK3
- dedicator of cytokinesis 3
- IDE
- insulin-degrading enzyme
- TRA2B
- transformer-2 protein homolog beta
- SNTG1
- synaptotagmin-1
- Hsp70
- heat-shock protein 70
- iPSCs
- induced pluripotent stem cells