TY  - JOUR
AU  - Agerschou, Emil Dandanell
AU  - Borgmann, Vera
AU  - Wördehoff, Michael M.
AU  - Hoyer, Wolfgang
TI  - Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein
JO  - Chemical science
VL  - 11
IS  - 41
SN  - 2041-6539
CY  - Cambridge
PB  - RSC
M1  - FZJ-2020-04791
SP  - 11331 - 11337
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000582936200022
DO  - DOI:10.1039/D0SC04051G
UR  - https://juser.fz-juelich.de/record/888242
ER  -