A SUMO1-Derived Peptide Targeting SUMO-Interacting Motif Inhibits ?-Synuclein Aggregation.

The accumulation of ?-synuclein amyloid fibrils in the brain is linked to Parkinson's disease and other synucleinopathies. The intermediate species in the early aggregation phase of ?-synuclein are involved in the emergence of amyloid toxicity and considered to be the most neurotoxic. The N-terminal region flanking the non-amyloid-? component domain ...
of ?-synuclein has been implicated in modulating its aggregation. Herein, we report the development of a SUMO1-derived peptide inhibitor (SUMO1(15-55)), which targets two SUMO-interacting motifs (SIMs) within this aggregation-regulating region and suppresses ?-synuclein aggregation. Molecular modeling, site-directed mutagenesis, and binding studies are used to elucidate the mode of interaction, namely, via the binding of either of the two SIM sequences on ?-synuclein to a putative hydrophobic binding groove on SUMO1(15-55). Subsequent studies show that SUMO1(15-55) also reduces ?-synuclein-induced cytotoxicity in cell-based and Drosophila disease models.
Mesh Terms:
Animals, Disease Models, Animal, Drosophila, Drug Discovery, Humans, Parkinson Disease, Peptides, Protein Aggregates, Protein Aggregation, Pathological, Protein Interaction Maps, SUMO-1 Protein, alpha-Synuclein
Cell Chem Biol
Date: Dec. 18, 2020
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