Book of Abstracts: Albany 2005
The Metal Ligands of Cu/Zn Superoxide Dismutase Display Cooperative Roles in its Kinetic Stabilization: Implications for Amyotrophic Lateral Sclerosis
A significant number of mutations in the enzyme Cu/Zn superoxide dismutase has been implicated in a familial form of the disease amyotrophic lateral sclerosis (ALS) (1). Growing evidence suggests that the aggregation of SOD mutants may play a causative role in FALS, and that aberrant copper chemistry, decreased thermodynamic stability, and decreased affinity for metals may contribute independently or synergistically to this process (2-4). It has been also shown that the loss of the metal cofactors zinc and copper thermodynamically and kinetically destabilizes the WT enzyme to a similar extent as the mutants (5, 6), thus predisposing it to misfold and aggregate into forms typical of the disease. In this work, the individual contributions of copper and zinc to the kinetic stability of SOD were investigated and found to be cooperative, with each metal bestowing only partial kinetic stability on the enzyme. Thus, loss of kinetic stability arising from the deficiency in either one of the metal cofactors suggests a means by which WT and mutant SOD may become susceptible to misfolding and aggregation, with potential implications for the pathogenic mechanism of ALS.
References and Footnotes
Sandra M. Lynch1
1Isermann Department of Chemical and Biological Engineering