Amyotrophic lateral sclerosis (ALS) is a devastating terminal illness characterized by sudden motor neuron degeneration that impacts thousands of people throughout the world. With no known cure and few treatments, it is vital that ALS be studied. ErbB4, a kinase receptor protein, has been linked to ALS through two point mutations localized in its kinase and cytoplasmic domains.

Due to the correlation between ALS and ErbB4’s pathway, our investigation sought to identify how the two mutations might interact with ErbB4’s structure as a whole by testing the experimental hypothesis that the mutations would affect ErbB4's proteolysis by the enzyme TACE/ADAM17. Since the location of TACE’s cut sites on ErbB4 is unknown, the experiment involved analyzing the known cleavage sites of fourteen TACE substrates for common structures and amino acid residue patterns. Using this data, we found two potential cleavage sites in ErbB4’s sequence. Neither potential cleavage site was near the mutations in the sequence, so we visualized ErbB4’s three-dimensional structure in PyMOL to determine how the mutations and possible cleavage sites might interact. However, the first mutation was located in ErbB4’s kinase domain, near a ligand binding site, and in a section of ErbB4 containing a different secondary structure depending on whether or not it was activated. It appears to be unlikely that the ALS-associated mutations impact ErbB4’s proteolysis by TACE, but the kinase domain and ligand binding site within it seem to be a promising place for further investigation.