Targeted degradation of α-Synuclein using an evolved botulinum toxin protease.

ABSTRACT: There is considerable interest in the targeted degradation of proteins implicated in human disease. The use of sequence-specific proteases for this purpose is severely limited by the difficulty in engineering the numerous enzyme-substrate interactions required to yield highly selective proteases while maintaining catalytic activity. Herein, we report a strategy to evolve a protease for the programmed degradation of α-Synuclein, a presynaptic protein closely linked to Parkinson's disease. Our structure-guided evolution campaign uses the protease from botulinum neurotoxin and showcases the stepwise change of specificity from its native substrate SNAP25 to the selective degradation of α-Synuclein. The protease's selectivity is further demonstrated in human cells where near complete degradatio

SUBMITTER: Sondermann P 

PROVIDER: S-EPMC12002255 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature