Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the death of the upper and lower motor neurons. Superoxide dismutase 1 (SOD1) is an ALS pathogenic protein, whose misfolding results in the formation of amyloid aggregates. The mechanism underlying SOD1 pathogenesis in ALS remains obscure, but one possible mechanism involves gain-of-interaction, in which the misfolded soluble SOD1 forms abnormal protein-protein interactions (PPIs) with various cellular proteins, including with other SOD1 molecules, thereby interfering with their function. The structural basis of this gain-of-interaction mechanism is unknown. Here, we characterized the backbone dynamics landscape of misfolded SOD1 to pinpoint surface areas predisposed to aberrant PPIs. This analysis enabled us to formulate a working hypothesis for the mechanism of the gain-of-function of misfolded SOD1, according to which an abnormal PPI potential results from the increased mobility of the SOD1 surface backbone. Guided by the backbone dynamics landscape, we have identified a SOD1-derived peptide that can bind SOD1 proteins and divert the typical amyloid aggregation of ALS-related SOD1 mutants toward a potentially less toxic amorphous aggregation pathway.
Keywords: Amyotrophic lateral sclerosis (ALS); amyloid aggregation; gain-of-function; stability patches; steered molecular dynamics (SMD); superoxide dismutase 1 (SOD1).