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 - Funding Information:
This work was supported in part by National Institutes of Health Grants R01 GM110755, R01 GM054803, R01 NS39112, R01 GM112763, and R01 GM120252 (to D. R. W., N. J. B., P. J. H., J. A. W., and D. D. W., respectively); United States Department of Veterans Affairs Merit Review Award I01 BX002580 (to P. J. H.); and Robert A. Welch Foundation Grant AQ-1399 (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the United States government, or the National Institutes of Health. Supported by National Institutes of Health Training Grant T32 DK007115. We thank Dr. Val Culotta for generously providing numerous reagents. Support for Northeastern Collaborative Access Team beamline 24-ID-E is provided by National Institutes of Health Grant P41 GM103403 and United States Department of Energy Grant DE-AC02-06CH11357. The X-Ray Crystallography Core Laboratory at the University of Texas Health Science Center at San Antonio is supported in part by the Office of the Vice President for Research and by San Antonio Cancer Institute Grant P30 CA054174. Use of the Stanford Synchrotron Radiation Lightsource, Stanford Linear Accelerator Center National Accelerator Laboratory, is supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The Stanford Synchrotron Radiation Lightsource Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including Grant P41GM103393).
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 -