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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 (UGent) , Vera Goossens (UGent) , Dietmar Rudolf Thal, et al.
(2022) NATURE COMMUNICATIONS. 13(1).
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Abstract
In this work, Louros et al. uncover a rule book for interactions of amyloids with other proteins. This grammar was shown to promote cellular spreading of tau aggregates in cells, but can also be harvested to develop structure-based aggregation blockers. 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.
Keywords
General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, SELECTIVE NEURONAL VULNERABILITY, STRUCTURE-BASED INHIBITORS, INSULIN-DEGRADING ENZYME, CRYO-EM STRUCTURES, ALZHEIMERS-DISEASE, NEURODEGENERATIVE DISEASES, A-BETA, PROTEIN AGGREGATION, CELL-DEATH, IN-VIVO

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MLA
Louros, Nikolaos, et al. “Mapping the Sequence Specificity of Heterotypic Amyloid Interactions Enables the Identification of Aggregation Modifiers.” NATURE COMMUNICATIONS, vol. 13, no. 1, 2022, doi:10.1038/s41467-022-28955-9.
APA
Louros, N., Ramakers, M., Michiels, E., Konstantoulea, K., Morelli, C., Garcia, T., … Schymkowitz, J. (2022). Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers. NATURE COMMUNICATIONS, 13(1). https://doi.org/10.1038/s41467-022-28955-9
Chicago author-date
Louros, Nikolaos, Meine Ramakers, Emiel Michiels, Katerina Konstantoulea, Chiara Morelli, Teresa Garcia, Nele Moonen, et al. 2022. “Mapping the Sequence Specificity of Heterotypic Amyloid Interactions Enables the Identification of Aggregation Modifiers.” NATURE COMMUNICATIONS 13 (1). https://doi.org/10.1038/s41467-022-28955-9.
Chicago author-date (all authors)
Louros, Nikolaos, 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. 2022. “Mapping the Sequence Specificity of Heterotypic Amyloid Interactions Enables the Identification of Aggregation Modifiers.” NATURE COMMUNICATIONS 13 (1). doi:10.1038/s41467-022-28955-9.
Vancouver
1.
Louros N, Ramakers M, Michiels E, Konstantoulea K, Morelli C, Garcia T, et al. Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers. NATURE COMMUNICATIONS. 2022;13(1).
IEEE
[1]
N. Louros et al., “Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers,” NATURE COMMUNICATIONS, vol. 13, no. 1, 2022.
@article{8748387,
  abstract     = {{In this work, Louros et al. uncover a rule book for interactions of amyloids with other proteins. This grammar was shown to promote cellular spreading of tau aggregates in cells, but can also be harvested to develop structure-based aggregation blockers.

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.}},
  articleno    = {{1351}},
  author       = {{Louros, Nikolaos and Ramakers, Meine and Michiels, Emiel and Konstantoulea, Katerina and Morelli, Chiara and Garcia, Teresa and Moonen, Nele and D'Haeyer, Sam and Goossens, Vera and Thal, Dietmar Rudolf and Audenaert, Dominique and Rousseau, Frederic and Schymkowitz, Joost}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{General Physics and Astronomy,General Biochemistry,Genetics and Molecular Biology,General Chemistry,SELECTIVE NEURONAL VULNERABILITY,STRUCTURE-BASED INHIBITORS,INSULIN-DEGRADING ENZYME,CRYO-EM STRUCTURES,ALZHEIMERS-DISEASE,NEURODEGENERATIVE DISEASES,A-BETA,PROTEIN AGGREGATION,CELL-DEATH,IN-VIVO}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{20}},
  title        = {{Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers}},
  url          = {{http://doi.org/10.1038/s41467-022-28955-9}},
  volume       = {{13}},
  year         = {{2022}},
}
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