Journal Article

FZJ-2020-04791

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

Agerschou, E. D. ; Borgmann, V. ; Wördehoff, M. M. ; Hoyer, W. (Corresponding author)FZJ*

2020
RSC Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/26801  doi:10.1039/D0SC04051G

Abstract: In amyloid fibril elongation, soluble growth substrate binds to the fibril-end and converts into the fibril conformation. This process is targeted by inhibitors that block fibril-ends. Here, we investigated how the elongation of α-synuclein (αS) fibrils, which are associated with Parkinson's disease and other synucleinopathies, is inhibited by αS variants with a preformed hairpin in the critical N-terminal region comprising residues 36–57. The inhibitory efficiency is strongly dependent on the specific position of the hairpin. We find that the inhibitor and substrate concentration dependencies can be analyzed with models of competitive enzyme inhibition. Remarkably, the growth substrate, i.e., wild-type αS, supports inhibition by stabilizing the elongation-incompetent blocked state. This observation allowed us to create inhibitor–substrate fusions that achieved inhibition at low nanomolar concentration. We conclude that inhibitor–substrate cooperativity can be exploited for the design of fibril growth inhibitors.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)
2. BETACONTROL - Control of amyloid formation via beta-hairpin molecular recognition features (726368) (726368)

Appears in the scientific report 2020

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Database coverage:
; ; ; ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; National-Konsortium ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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