TY - JOUR
T1 - Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site
AU - Fetherolf, Morgan M.
AU - Boyd, Stefanie D.
AU - Taylor, Alexander B.
AU - Kim, Hee Jong
AU - Wohlschlegel, James A.
AU - Blackburn, Ninian J.
AU - Hart, P. John
AU - Winge, Dennis R.
AU - Winkler, Duane D.
N1 - Publisher Copyright:
© 2017, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.
PY - 2017/7/21
Y1 - 2017/7/21
N2 - Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed “entry site” for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond-requiring enzyme in the cytoplasm, and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.
AB - Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed “entry site” for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond-requiring enzyme in the cytoplasm, and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.
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U2 - 10.1074/jbc.M117.775981
DO - 10.1074/jbc.M117.775981
M3 - Article
C2 - 28533431
AN - SCOPUS:85025175819
SN - 0021-9258
VL - 292
SP - 12025
EP - 12040
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -