A paper published!(論文発表)


SOD1 mutations are one of the causes of amyotrophic lateral sclerosis (ALS), and mutations (E40K) in the SOD1 gene in dogs also cause degenerative myelopathy (DM), a motor neuron disease similar to ALS. Like ALS, mutation-induced amino acid substitution (E40K) is considered to affect the structure of canine SOD1 (cSOD1) and cause the disease; however, the details are not clear. In this study, Prof. Koji Yamanaka’s group at Nagoya University found that when methionine, the 117th amino acid of cSOD1, is replaced with leucine, the structural abnormality of cSOD1 caused by E40K mutation is not observed. Therefore, our group performed crystallographic analysis to clarify the reason why the E40K-cSOD1 structural abnormality is not observed by the M117L mutation. As a result, the methionine is located in the hydrophobic core of the cSOD1 structure but also creates a void in its vicinity. On the other hand, substitution of leucine, a hydrophobic amino acid slightly larger in size than methionine, was found to fill the void exactly (see figure below), which is considered to result in the structural stabilization of cSOD1. Since the 117th amino acid in human SOD1 is leucine, canine SOD1 is more structurally unstable than human SOD1 and also more vulnerable to amino acid substitutions such as E40K. You can find details here.