Amyotrophic lateral
sclerosis (ALS) is a fatal, incurable neurodegenerative
disease described by progressive degeneration of motor neurons. The
most common familial form of ALS (fALS) has been associated with mutations
in the Cu/Zn superoxide dismutase (SOD1) gene. Mutation-induced
misfolding and aggregation of SOD1 is often found in ALS patients.
In this work, we probe the aggregation properties of peptides derived
from the SOD1. To examine the source of SOD1 aggregation, we have
employed a computational algorithm to identify four peptides from
the SOD1 protein sequence that aggregates into a fibril. Aided by
computational algorithms, we identified four peptides likely involved
in SOD1 fibrillization. These four aggregation-prone peptides were 14VQGIINFE21, 30KVWGSIKGL38, 101DSVISLS107, and 147GVIGIAQ153. In addition,
the formation of fibril propensities from the identified peptides
was investigated through different biophysical techniques. The atomic
structures of two fibril-forming peptides from the C-terminal SOD1
showed that the steric zippers formed by 101DSVISLS107 and 147GVIGIAQ153 vary in their arrangement.
We also discovered that fALS mutations in the peptide 147GVIGIAQ153 increased the fibril-forming propensity and
altered the steric zipper’s packing. Thus, our results suggested
that the C-terminal peptides of SOD1 have a central role in amyloid
formation and might be involved in forming the structural core of
SOD1 aggregation observed in vivo.