Cross-Linked α-Synuclein as Inhibitor of Amyloid Formation.

Autor: Murvai N; Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.; ELTE-Functional Nucleic Acid Motifs Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary., Gellen G; MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.; Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.; Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary., Micsonai A; Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.; ELTE-Functional Nucleic Acid Motifs Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.; ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary., Schlosser G; MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary., Kardos J; Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.; ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Aug 29; Vol. 24 (17). Date of Electronic Publication: 2023 Aug 29.
DOI: 10.3390/ijms241713403
Abstrakt: The aggregation and amyloid formation of α-synuclein is associated with Parkinson's disease and other synucleinopathies. In its native, monomeric form α-synuclein is an intrinsically disordered protein represented by highly dynamic conformational ensembles. Inhibition of α-synuclein aggregation using small molecules, peptides, or proteins has been at the center of interest in recent years. Our aim was to explore the effects of cross-linking on the structure and aggregation/amyloid formation properties of α-synuclein. Comparative analysis of available high-resolution amyloid structures and representative structural models and MD trajectory of monomeric α-synuclein revealed that potential cross-links in the monomeric protein are mostly incompatible with the amyloid forms and thus might inhibit fibrillation. Monomeric α-synuclein has been intramolecularly chemically cross-linked under various conditions using different cross-linkers. We determined the location of cross-links and their frequency using mass spectrometry and found that most of them cannot be realized in the amyloid structures. The inhibitory potential of cross-linked proteins has been experimentally investigated using various methods, including thioflavin-T fluorescence and transmission electron microscopy. We found that conformational constraints applied by cross-linking fully blocked α-synuclein amyloid formation. Moreover, DTSSP-cross-linked molecules exhibited an inhibitory effect on the aggregation of unmodified α-synuclein as well.
Databáze: MEDLINE
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