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

Nikolaos Louros, Meine Ramakers, Emiel Michiels, Katerina Konstantoulea, Chiara Morelli, Teresa Garcia, Nele Moonen, Sam D’Haeyer, Vera Goossens, Dietmar Rudolf Thal, Dominique Audenaert, Frederic Rousseau () and Joost Schymkowitz ()
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Nikolaos Louros: Switch Laboratory, VIB Center for Brain and Disease Research
Meine Ramakers: Switch Laboratory, VIB Center for Brain and Disease Research
Emiel Michiels: Switch Laboratory, VIB Center for Brain and Disease Research
Katerina Konstantoulea: Switch Laboratory, VIB Center for Brain and Disease Research
Chiara Morelli: Switch Laboratory, VIB Center for Brain and Disease Research
Teresa Garcia: Switch Laboratory, VIB Center for Brain and Disease Research
Nele Moonen: Switch Laboratory, VIB Center for Brain and Disease Research
Sam D’Haeyer: VIB Screening Core
Vera Goossens: VIB Screening Core
Dietmar Rudolf Thal: KU Leuven, Leuven Brain Institute
Dominique Audenaert: VIB Screening Core
Frederic Rousseau: Switch Laboratory, VIB Center for Brain and Disease Research
Joost Schymkowitz: Switch Laboratory, VIB Center for Brain and Disease Research

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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 tau as a model system we demonstrate that proteins with local sequence homology to tau amyloid nucleating regions can modify fibril nucleation, morphology, assembly and spreading of aggregates in cultured cells. Depending on the type of mutation such interactions inhibit or promote aggregation in a manner that can be predicted from structure. We find that these heterotypic amyloid interactions can result in the subcellular mis-localisation of these proteins. Moreover, equilibrium studies indicate that the critical concentration of aggregation is altered by heterotypic interactions. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and we discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.

Date: 2022
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DOI: 10.1038/s41467-022-28955-9

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