Issue 41, 2020

Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

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.

Graphical abstract: Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

Supplementary files

Article information

Article type
Edge Article
Submitted
24 7月 2020
Accepted
28 9月 2020
First published
28 9月 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2020,11, 11331-11337

Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

E. D. Agerschou, V. Borgmann, M. M. Wördehoff and W. Hoyer, Chem. Sci., 2020, 11, 11331 DOI: 10.1039/D0SC04051G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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