Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

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.

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

“…CBD and PSP or AD and CTE) still adopt different filament folds indicating that other factors also shape the diversity of tau filament folds 20,33 . Disease-specific post-translational modifications 31 , as well as other physiopathological cellular interactions probably play an important role for the maturation of pathological tau into disease specific polymorphs 8,34 .…”

“…Following approval, brain tissue from autopsy cases was received from UZ/KU Leuven Biobank. Sarkosyl-insoluble material was extracted from cortex tissue of three individual patients with Alzheimer’s disease (AD1 – AD3), as described in previous work 8,50 . Tissue homogenisation was performed with a FastPrep (MP Biomedicals) in 10 volumes (w/v) cold buffer (10 mM Tris-HCl pH 7.4, 0.8 M NaCl, 1 mM EGTA and 10% sucrose) and a centrifugation step at 20,000 x g for 20 min at 4°C.…”

“…It is currently suspected that tau amyloids or their precursors aberrantly interact with cellular components including lipids, nucleic acids and proteins, leading to their functional dysregulation 8,9 . Tau amyloid deposits may also sequester other cellular components leading to neuronal impairment and cell death 8 . Different tauopathies originate in different brain regions and neuronal cell types, resulting in distinct spatio-temporal disease progressions and neuropathological symptoms 10 , suggesting that the pathological mechanisms underlying neurodegeneration may vary between tauopathies.…”

“…The exact role of tau amyloid deposition and spreading in neuronal cell death remains unclear. It is currently suspected that tau amyloids or their precursors aberrantly interact with cellular components including lipids, nucleic acids and proteins, leading to their functional dysregulation 8,9 . Tau amyloid deposits may also sequester other cellular components leading to neuronal impairment and cell death 8 .…”

PACT - Prediction of Amyloid Cross-interaction by Threading

“…These results suggest that both processes may be driven by similar mechanisms. This issue was addressed in a recently published work by Louros and coworkers ( Louros et al, 2022 ), who applied a somewhat similar approach to study the effect of point mutations on aggregation characteristics.…”