Dokument: The role of b-hairpins in protein aggregation
| Titel: | The role of b-hairpins in protein aggregation | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=64598 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240115-093609-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Heid, Laetitia [Autor] | |||||||
| Dateien: |
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| Beitragende: | Dr. Wolfgang Hoyer [Gutachter] Prof. Dr. Kurz, Thomas [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | The b-hairpin is a common motif in protein folds and represents the smallest possible b-sheet.
It consists of two b-strands that are connected by a turn and align in an antiparallel fashion, which allows formation of backbone hydrogen bonds as well as interactions among side chains in the neighboring strands. b-Hairpins are spread throughout all living species and building blocks of larger b-sheets. b-Hairpins have gained interest in the research field of the diseases that involve amyloids. If two or more b-strands form hydrogen bonds between each other b- sheets begin to build. In amyloid diseases, such b-sheets grow in length along the fibril axis until they form extremely stable fibrils that, despite the involvement of different proteins with widely different sequences, have a highly consistent morphology consisting of a cross-b- structure where the parallel b-strands run perpendicular to the fibril axis. Such amyloid fibrils are linked to many diseases, in particular neurodegenerative diseases and non-neuropathic systemic amyloidosis. In the projects of this thesis, different b-hairpins were identified and characterized, with regard to their role in amyloid formation and to their interaction with engineered binding proteins. One project explores how widespread amyloidogenic b-hairpins are in the human proteome. The second project aims to explore if amyloidogenic b-hairpins interfere with amyloid formation of sequence-unrelated proteins, to test if b-hairpins might contribute to the cross-b-interaction and cross-seeding phenomena previously described for different amyloid systems. In a third project the aim was to optimize compounds that bind b-hairpins and can inhibit the amyloid formation on the protein and small molecule level. On the protein level that meant to optimize the b-wrapin AS69, that can bind a-synuclein in a coupled-folded binding mode and optimize it via molecular dynamics simulation and characterize those new constructs via isothermal titration calorimetry. On the other hand, to approach the inhibition of a-synuclein aggregation with small molecules first steps to develop a high throughput screening assay have been taken to be able to identify the correct molecules that can bind the a-synuclein b-hairpin. In a fourth project the expression and purification of two model proteins for light-chain amyloidosis was established with sequences that also carry a b-hairpin motif with the same characteristics as those found in for example a-synuclein. With an established expression and purification protocol the next step was to find the correct conditions for those two proteins to aggregate and to test the potential of b-wrapin AS10 to inhibit aggregation. The overall aim of this thesis is to further elucidate the role of b-hairpins in amyloid formation and delineate their potential to serve as targets in anti-amyloid inhibition approaches. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Physikalische Biologie | |||||||
| Dokument erstellt am: | 15.01.2024 | |||||||
| Dateien geändert am: | 15.01.2024 | |||||||
| Promotionsantrag am: | 27.09.2023 | |||||||
| Datum der Promotion: | 18.12.2023 |
