Cited by 28Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingProtein Structure and Dynamics

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

Open access
Louros, Nikolaos, Ramakers, Meine, Michiels, Emiel, Konstantoulea, Katerina, Morelli, Chiara, Garcia, Teresa, Moonen, Nele, D’Haeyer, Sam +5 more·2022·Nature Communications

Published version of a preprint

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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Crossref · 10.1038/s41467-022-28955-9

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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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Research works printed but not linked: 1

  1. [82]Banach, M. & Roterman, I. in From Globular Proteins to Amyloids (ed. Roterman-Konieczna, I.) 95–115 (Elsevier, 2020).

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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
Venue
Nature Communications
Published
2022-03-15
Volume
13
Issue
1
Pages
1351-1351
ISSN
2041-1723 (ISSN-L)
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
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

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