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Membrane mechanisms of nucleation and toxic action of protein aggregates involved in the development of conformational diseases

Work number - M 43 AWARDED

Author: TrusovaValeriyaMikhailivna

PresentedbyV.N. KarazinKharkivNationalUniversity

A series of research works contains priority findings concerning the role of protein-lipid interactions in pathological protein aggregation. A new approach allowing to estimate the structural parameters of amyloid fibrils, such as molecular volume of monomeric subunit and aggregate fractal dimension, by measuring the efficiency of resonance energy transfer between amyloid-specific fluorophores, has been suggested. Based on the complex interpretation of the steady-state and time-resolved FRET data a novel methodology for determination of the protein oligomerization extent on the lipid template has been developed. Using a range of fluorescent probes the effect of prefibrillar and fibrillar aggregates of lysozyme and N-terminal fragment of apolipoprotein A-I on the structure, dynamics and physicochemical properties of the model lipid membranes of various composition has been characterized. A new strategy for monitoring the topological modifications of fibrillar aggregates through Monte-Carlo analysis of FRET between the membrane-bound fluorophore and amyloid-specific dye has been proposed. Evidence for structural transformation of amyloif fibrils of N-terminal fragment of apolipoprotein A-I in the membrane environment has been obtained. The role of lipids in the formation of aggregation-competent conformational state of lysozyme, cytochrome c and N-terminal fragment of apolipoprotein A-I has been elucidated by molecular dynamics simulation.

The presented experimental and theoretical results may prove of importance for deeper understanding of the molecular mechanisms behind self-assembly of amyloid fibrils and their intermediates at the lipid-water interface and membrane-modifying properties of aggregated proteins. The investigated newly-synthesized amyloid-specific fluorescent probes can be employed for the elaboration of biosensor systems for early diagnostics of conformational diseases, as well as for structural characterization of amyloid fibrils. The data on the modifying effect of fibrillar aggregates on the structure and dynamics of lipid membranes are of significance for preventing the cytotoxic action of amyloid fibrils at the membrane level and development of the new strategies for searching the anti-amyloid drugs. The quantitative information on the mechanical properties of amyloid fibrils can be used for creation of the novel amyloid-based biocompatible nanomaterials for a variety of biomedical applications.

The results obtained are described in 112 works, including 2 chapters in collective monographs, 30 papers in refereed journals, 18 papers in the local journals, 2 patents of Ukraine. The total impact factor of these publications is 63.38. The total citation index is 333 according to Google Scholar and 271 according to Scopus, h-index is 7.