Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains
Heterologous interactions between different amyloid-forming proteins, also called cross-interactions, may have a critical impact on disease-related amyloid formation. β-hairpin conformers of amyloid-forming proteins have been shown to affect homologous interactions in the amyloid self-assembly proce...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/22/16132 |
| _version_ | 1797459075714252800 |
|---|---|
| author | Laetitia F. Heid Tatsiana Kupreichyk Marie P. Schützmann Walfried Schneider Matthias Stoldt Wolfgang Hoyer |
| author_facet | Laetitia F. Heid Tatsiana Kupreichyk Marie P. Schützmann Walfried Schneider Matthias Stoldt Wolfgang Hoyer |
| author_sort | Laetitia F. Heid |
| collection | DOAJ |
| description | Heterologous interactions between different amyloid-forming proteins, also called cross-interactions, may have a critical impact on disease-related amyloid formation. β-hairpin conformers of amyloid-forming proteins have been shown to affect homologous interactions in the amyloid self-assembly process. Here, we applied two β-hairpin-forming peptides derived from immunoglobulin light chains as models to test how heterologous β-hairpins modulate the fibril formation of Parkinson’s disease-associated protein α-synuclein (αSyn). The peptides SMAhp and LENhp comprise β-strands C and C′ of the κ4 antibodies SMA and LEN, which are associated with light chain amyloidosis and multiple myeloma, respectively. SMAhp and LENhp bind with high affinity to the β-hairpin-binding protein β-wrapin AS10 according to isothermal titration calorimetry and NMR spectroscopy. The addition of SMAhp and LENhp affects the kinetics of αSyn aggregation monitored by Thioflavin T (ThT) fluorescence, with the effect depending on assay conditions, salt concentration, and the applied β-hairpin peptide. In the absence of agitation, substoichiometric concentrations of the hairpin peptides strongly reduce the lag time of αSyn aggregation, suggesting that they support the nucleation of αSyn amyloid fibrils. The effect is also observed for the aggregation of αSyn fragments lacking the N-terminus or the C-terminus, indicating that the promotion of nucleation involves the interaction of hairpin peptides with the hydrophobic non-amyloid-β component (NAC) region. |
| first_indexed | 2024-03-09T16:46:13Z |
| format | Article |
| id | doaj.art-b5e57536a47747e69028e3d06809dc21 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:46:13Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b5e57536a47747e69028e3d06809dc212023-11-24T14:46:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221613210.3390/ijms242216132Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light ChainsLaetitia F. Heid0Tatsiana Kupreichyk1Marie P. Schützmann2Walfried Schneider3Matthias Stoldt4Wolfgang Hoyer5Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, GermanyInstitute of Biological Information Processing (IBI-7) and JuStruct, Jülich Center for Structural Biology, Forschungszentrum Jülich, 52425 Jülich, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, GermanyHeterologous interactions between different amyloid-forming proteins, also called cross-interactions, may have a critical impact on disease-related amyloid formation. β-hairpin conformers of amyloid-forming proteins have been shown to affect homologous interactions in the amyloid self-assembly process. Here, we applied two β-hairpin-forming peptides derived from immunoglobulin light chains as models to test how heterologous β-hairpins modulate the fibril formation of Parkinson’s disease-associated protein α-synuclein (αSyn). The peptides SMAhp and LENhp comprise β-strands C and C′ of the κ4 antibodies SMA and LEN, which are associated with light chain amyloidosis and multiple myeloma, respectively. SMAhp and LENhp bind with high affinity to the β-hairpin-binding protein β-wrapin AS10 according to isothermal titration calorimetry and NMR spectroscopy. The addition of SMAhp and LENhp affects the kinetics of αSyn aggregation monitored by Thioflavin T (ThT) fluorescence, with the effect depending on assay conditions, salt concentration, and the applied β-hairpin peptide. In the absence of agitation, substoichiometric concentrations of the hairpin peptides strongly reduce the lag time of αSyn aggregation, suggesting that they support the nucleation of αSyn amyloid fibrils. The effect is also observed for the aggregation of αSyn fragments lacking the N-terminus or the C-terminus, indicating that the promotion of nucleation involves the interaction of hairpin peptides with the hydrophobic non-amyloid-β component (NAC) region.https://www.mdpi.com/1422-0067/24/22/16132β-hairpincross-seedingsynucleinopathyAL amyloidosisprimary nucleationsecondary nucleation |
| spellingShingle | Laetitia F. Heid Tatsiana Kupreichyk Marie P. Schützmann Walfried Schneider Matthias Stoldt Wolfgang Hoyer Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains International Journal of Molecular Sciences β-hairpin cross-seeding synucleinopathy AL amyloidosis primary nucleation secondary nucleation |
| title | Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains |
| title_full | Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains |
| title_fullStr | Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains |
| title_full_unstemmed | Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains |
| title_short | Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains |
| title_sort | nucleation of α synuclein amyloid fibrils induced by cross interaction with β hairpin peptides derived from immunoglobulin light chains |
| topic | β-hairpin cross-seeding synucleinopathy AL amyloidosis primary nucleation secondary nucleation |
| url | https://www.mdpi.com/1422-0067/24/22/16132 |
| work_keys_str_mv | AT laetitiafheid nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains AT tatsianakupreichyk nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains AT mariepschutzmann nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains AT walfriedschneider nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains AT matthiasstoldt nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains AT wolfganghoyer nucleationofasynucleinamyloidfibrilsinducedbycrossinteractionwithbhairpinpeptidesderivedfromimmunoglobulinlightchains |