A Substantial Structural Conversion of the Native Monomer Leads to in-Register Parallel Amyloid Fibril Formation in Light-Chain Amyloidosis
| Autor: | Beat H. Meier, Anja Böckmann, Thomas Wiegand, Luis del Pozo-Yauner, Guillermo A. Herrera, Riccardo Cadalbert, Francisco Javier Rodríguez-Alvarez, Lauriane Lecoq |
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| Přispěvatelé: | Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Physical Chemistry [ETH Zürich], Department of Chemistry and Applied Biosciences [ETH Zürich] (D-CHAB), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich) |
| Rok vydání: | 2018 |
| Předmět: |
Amyloid
Protein Folding Magnetic Resonance Spectroscopy Supramolecular chemistry macromolecular substances 010402 general chemistry Fibril Immunoglobulin light chain 01 natural sciences Biochemistry Turn (biochemistry) amyloidosis light chains NMR spectroscopy protein folding solid-state structures [CHIM.ANAL]Chemical Sciences/Analytical chemistry medicine Humans Molecular Biology ComputingMilieux_MISCELLANEOUS 010405 organic chemistry Chemistry Amyloidosis Organic Chemistry Nuclear magnetic resonance spectroscopy medicine.disease 0104 chemical sciences [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Biophysics Molecular Medicine Protein folding Immunoglobulin Light Chains Protein Conformation beta-Strand |
| Zdroj: | ChemBioChem, 20 (8) ChemBioChem ChemBioChem, Wiley-VCH Verlag, 2019, 20 (8), pp.1027-1031. ⟨10.1002/cbic.201800732⟩ |
| ISSN: | 1439-7633 1439-4227 |
| DOI: | 10.1002/cbic.201800732⟩ |
| Popis: | Amyloid light-chain (AL) amyloidosis is a rare disease in which plasma-cell-produced monoclonal immunoglobulin light chains misfold and become deposited as fibrils in the extracellular matrix. λ6 subgroup light chains are particularly fibrillogenic, and around 25 % of amyloid-associated λ6 light chains exist as the allotypic G24R variant that renders the protein less stable. The molecular details of this process, as well as the structures of the fibrils, are unknown. We have used solid-state NMR to investigate different fibril polymorphs. The secondary structures derived from NMR predominantly show β-strands, including in former turn or helical regions, and provide a molecular basis for previously identified fibrillogenic hotspots. We have determined, by using differentially 15 N:13 C-labeled samples, that the β-strands are stacked in-register parallel in the fibrils. This supramolecular arrangement shows that the native globular folds rearrange substantially upon fibrillization, and rules out the previously hypothesized fibril formation from native monomers. |
| Databáze: | OpenAIRE |
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