PT  - JOURNAL ARTICLE
AU  - Nikolaos Louros
AU  - Meine Ramakers
AU  - Emiel Michiels
AU  - Katerina Konstantoulea
AU  - Chiara Morelli
AU  - Teresa Garcia
AU  - Sam D’Haeyer
AU  - Vera Goossens
AU  - Dominique Audenaert
AU  - Frederic Rousseau
AU  - Joost Schymkowitz
TI  - Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers
AID  - 10.1101/2021.06.04.447096
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.04.447096
4099  - http://biorxiv.org/content/early/2021/07/30/2021.06.04.447096.short
4100  - http://biorxiv.org/content/early/2021/07/30/2021.06.04.447096.full
AB  - 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 StatementThe authors have declared no competing interest.APRsaggregation prone regionsPCAprincipal component analysisUMAPuniform manifold approximation and projectionADalzheimer’s diseasePDparkinson’s DiseaseAβbeta-amyloid peptideApo-AIapolipoprotein A-IHA-taghuman influenza hemagglutinin tagIRESinternal ribosome entry sitePHFpair helical fragmentCFPcyan-fluorescent proteinYFPyellow-fluorescent proteinFRETFörster resonance energy transferCBDcorticobasal degenerationCJDCreutzfeldt-Jakob diseaseFTDfrontotemporal dementiaTEMtransmission Electron MicroscopyFTIRFourier-transform infrared spectroscopycryo-EMcryogenic electron microscopyNMRnuclear magnetic resonanceCMVcytomegalovirusPVDFpolyvinylidene fluorideFRAPfluorescence recovery after photobleachingT2Dtype-2 diabetesRP-HPLCreverse-phase high-performance liquid chromatographyBSAbovine serum albuminNHSsuccinimidyl esterDOCK3dedicator of cytokinesis 3IDEinsulin-degrading enzymeTRA2Btransformer-2 protein homolog betaSNTG1synaptotagmin-1Hsp70heat-shock protein 70iPSCsinduced pluripotent stem cells