Collapsed Structure at the C‐Terminus of SOD1: Implications for ALS

Aggregates of Cu, Zn Superoxide Dismutase (SOD1) in the spinal cord are a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal motor neuron degeneration disorder. SOD1 is a homodimeric protein in which each monomer consists of a 153‐residue 8 stranded antiparallel β‐sandwich with a disulfide bond linking loop IV to β8. Many mutations throughout the sequence have been found to cause ALS, suggesting a general mechanism for this gain of function disease. Recent work from our lab has demonstrated friction‐limited folding and unfolding after reduction of the disulfide bond. As the loss of the disulfide bond has been shown to lead to significantly increased populations of unfolded protein, we supposed that reduction of the disulfide bond may also allow the formation of non‐native intermolecular interactions that could lead to aggregation. To test this hypothesis, we dissected SOD1 into five peptides, each roughly 30 amino acids long, that were labelled with FRET acceptors and donors at or near the N/C‐termini. Only the C‐terminal peptide was found to collapse in water. Maximum Entropy Modeling of the time‐resolved FRET data and all‐atom Replica Exchange Molecular Dynamics simulations show that this peptide forms multiple collapsed structures. A subset of these structures may play a role in seeding the aggregation process of SOD1 in ALS pathologies.