Post-Translational Activation of SOD1 Regulated by Oxygen and
CCS.
Nina Brown, Andrew Torres, Yoshiaki Furukawa, Thomas
O'Halloran
Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL
60208, U.S.A. (nmbrown@chem.northwestern.edu)
The role of reactive oxygen species (ROS) as biological signaling
molecules is a rapidly expanding field; however, ROS have also been
implicated in the pathology of neurodegenerative diseases and cancer.
The emerging picture is not one of total elimination of cellular
reactive species, but of maintaining a balance between health and
toxicity. Oxidative stress leads to the up-regulation of many
antioxidant enzymes including Cu, Zn superoxide dismutase (SOD1) via
transcriptional mechanisms; however, few examples of post-translational
regulation are known. The copper chaperone for Sod1 (CCS), is required
for physiological Sod1 activity and its primary function is thought to
be delivery of copper to the enzyme. Data presented here are consistent
with a new function for CCS, namely mediating Sod1 enzyme activation in
response to changes in oxygen tension. Activity assays with pure
proteins and yeast cell extract reveal that O2 (or superoxide) is
essential for activation of Sod1 by CCS. Dose response studies using a
translational blocking agent demonstrate that the cellular oxidative
response to O2 is multi-tiered: existing apo-pools of Sod1 are activated
by CCS in the early response, followed by increasing expression of Sod1
protein with persistent oxidative assault. This CCS function provides
oxidant-responsive post-translational regulation of Sod1 activity and
may be relevant to a wide array of physiological stresses that involve a
sudden elevation of oxygen availability.