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001021671 1001_ $$0P:(DE-HGF)0$$aSchulz, Celina M.$$b0
001021671 245__ $$aFibril core regions in engineered α-synuclein dimer are crucial for blocking of fibril elongation
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001021671 520__ $$aSynucleinopathies like Parkinson's disease are neurodegenerative diseases which are associated with the deposition of fibrillar aggregates of the endogenous protein α-synuclein (α-syn). The inhibition of the elongation of α-syn fibrils is of great scientific interest and an option in the design of therapeutic strategies. Previously, we developed a disulfide-containing mutant of α-syn, called CC48, which inhibits fibril elongation by blocking of fibril ends. Surprisingly, wildtype (WT) α-syn molecules supported the blocked state, and a fusion of CC48 with WT α-syn, denoted WT-CC48, exhibited increased inhibitory potential. Here, we studied which regions of WT-CC48 are responsible for the strong inhibitory effect. To this end, we investigated a set of truncated versions of WT-CC48 by kinetic elongation assays, density gradient centrifugation, and atomic force microscopy. We show that in both the WT and the CC48 part of the fusion construct the hairpin region (residue 32-60) and NAC region (61-95), but not N- and C-terminal regions, are required for strong inhibition of fibril elongation. The required regions correspond to the segments forming the β-sheet core of α-syn fibrils. As α-syn fibrils typically consist of two protofilaments, the dimeric construct WT-CC48 provides the critical regions sufficient to cover the full β-sheetcore interface exposed at the fibril end, which can explain its high inhibitory efficiency. We suggest a mechanistic model of CC48-mediated inhibition of fibril elongation in which CC48 and WT α-syn cooperatively form an oligomer-like cap at the amyloid fibril end.
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001021671 7001_ $$0P:(DE-HGF)0$$aPfitzer, Anne$$b1
001021671 7001_ $$0P:(DE-Juel1)201143$$aHoyer, Wolfgang$$b2$$eCorresponding author$$ufzj
001021671 773__ $$0PERI:(DE-600)3063510-X$$a10.1016/j.bbadva.2023.100110$$gVol. 4, p. 100110 -$$p100110 -$$tBBA advances$$v4$$x2667-1603$$y2023
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