IMPAIRED COPPER-BINDING BY THE H46R MUTANT OF HUMAN CU,ZN SUPEROXIDE-DISMUTASE, INVOLVED IN AMYOTROPHIC-LATERAL-SCLEROSIS

Several point mutations in the gene coding for human Cu,Zn superoxide dismutase have been reported as being responsible for familial amyotro phic lateral sclerosis (FALS). However, no direct demonstration has be en provided for a correlation between total superoxide dismutase activ ity and severity of the FALS pathology. In order to get a better insig ht into the mechanism(s) underlying the FALS phenotype, we have invest igated the activity and the copper binding properties of the single mu tant H46R, which is associated with a Japanese form of FALS. We have s hown that this mutant is structurally stable but lacks significant enz yme activity and has impaired capability of binding catalytic copper. The mutant protein can be fully reconstituted with copper in vitro but its ESR spectrum displays an axial shape quite different from that of the wild-type.