期刊
MOLECULES
卷 25, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/molecules25112716
关键词
fatty acids; neurodegeneration; NMR spectroscopy; protein-lipid interactions; protein aggregation; Tau
资金
- GIDRM/Anna Laura Segre fellowship
- CooperInt Program of the University of Verona
- project INSPIRED-The National Research Infrastructures on Integrated Structural Biology, Drug Screening Efforts and Drug target functional characterization (NSRF 2014-2020) [MIS 5002550]
- project INSPIRED-The National Research Infrastructures on Integrated Structural Biology, Drug Screening Efforts and Drug target functional characterization (European Regional Development Fund) [MIS 5002550]
Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized. Methods: In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau(4RD), the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau(4RD)/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, alpha -synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau(4RD) and of alpha -synuclein. Conclusions: This study describes the reciprocal influence that Tau(4RD) and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly.
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