Abstract
Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxides. A wide range of SOD1 variants are linked to inherited, or familial, amyotrophic lateral sclerosis, a progressive and fatal neurodegenerative disease. Aberrant SOD1 oligomerization has been strongly implicated in disease causation, even for sporadic ALS, or SALS, which accounts for ~90% of ALS cases. Small heat shock proteins (sHSP) have been shown to protect against amyloid fibril formation in vitro, and the sHSP αB-crystallin suppresses in vitro aggregation of SOD1. We are seeking to elucidate the structural features of both SOD1 amyloid formation and αB-crystallin amyloid suppression. Specifically, we have used a flexible docking protocol to refine our model of a SOD1 non-obligate tetramer, postulated to function as a transient desolvating complex. Homology modeling and molecular dynamics (MD) are used to supply the missing structural elements of a previously characterized SOD1 amyloid filament, thereby providing a structural analysis for the observed gain of interaction. This completed filament is then further modified using MD to provide a structural model for protofibril capping of SOD1 filaments by αB-crystallin.
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