Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers
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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.
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Destabilization of cross-sectional interfaces was identified as a major contributing factor.
“The destabilization of cross-sectional interfaces was identified as a major contributing factor (67).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [67]
Aromatics and long positively charged side chains were effective in facilitating heterotypic capping due to steric clashes and charge repulsions.
“Amongst others, it was found that aromatics and long positively charged side chains were effective in facilitating heterotypic capping due to steric clashes and charge repulsions that countered further elongation.”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [67]
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Self-citationDe novo design of a biologically active amyloid
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Atomic Structures Suggest Determinants of Transmission Barriers in Mammalian Prion Disease
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Intrinsic aggregation propensity of the CsgB nucleator protein is crucial for curli fiber formation
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A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?
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Solenoid – An amyloid under control
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- [82]Banach, M. & Roterman, I. in From Globular Proteins to Amyloids (ed. Roterman-Konieczna, I.) 95–115 (Elsevier, 2020).
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TAF15 amyloids propagate via defined motifs in a prion-like fashion
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- Authors
- Louros, N., Ramakers, M., Michiels, E., Konstantoulea, K., Morelli, C., Garcia, T., Moonen, N., D’Haeyer, S., Goossens, V., Thal, D. R., Audenaert, D., Rousseau, F., & Schymkowitz, J.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Ghent University (BE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Schymkowitz, Joost
- ORCID
- Venue
- Nature Communications
- Published
- 2022-03-15
- Volume
- 13
- Issue
- 1
- Pages
- 1351-1351
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8924238
- OpenAlex
- W4221035740
- Cited by
- 28
- References
- 136
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 1
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lirias (submittedVersion, cc-by)
- Funders
- Agentschap Innoveren en Ondernemen
- Fonds Wetenschappelijk Onderzoek (G065721N, AKUL/097/037, G053420N, AH2016.133, 12P0919N and 12P0922N, G0F8516N, 12P0922N, G0H1716N, 12P0919N, G0C0320N, G0C2818N, AKUL/15/34, I011620N)
- KU Leuven
- Vlaams Instituut voor Biotechnologie (G0C2818N, G0C0320N, G053420N)
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- protein aggregation, sequence specificity, tau protein, amyloid nucleation, sequence homology, fibril morphology, critical concentration, proteostasis
- MeSH terms
- Amino Acid Sequence, Amyloid, Amyloidosis, Humans, Proteomics, Amyloidogenic Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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