Insights into the Role of the Unusual Disulfide Bond in Copper-Zinc Superoxide Dismutase

Sea, Kevin; Sohn, Suk Ho; Durazo, Armando; Sheng, Yinghong; Shaw, Bryan F.; Cao, Xiaoguang; Taylor, Alexander B.; Whitson, Lisa J.; Holloway, S.; Hart, P. John; Cabelli, Diane E.; Gralla, Edith Butler; Valentine, Joan Selverstone

doi:10.1074/jbc.m114.588798

Cited by 71 publications

(51 citation statements)

References 58 publications

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“…Delivery is achieved exclusively when disulfide formation occurs; thus, it appears that stability of Cu(I) bound at the active site in mature SOD1 is modulated by both oxidation of the coordinating thiolate ligand in the entry site (Cys-57) (preventing Cu(I) coordination) as well as possible structural constrains imposed to the active site by the disulfide bridge formation. This fits well with previous work showing that C57S and C146S SOD1 variants isolated from yeast show negligible active site Cu and an overabundance of Zn (ϳ2 Zn ions/SOD1 monomer) (53).…”

Section: Chaperoning Roles For Ccs1supporting

confidence: 92%

The yeast copper chaperone for copper-zinc superoxide dismutase (CCS1) is a multifunctional chaperone promoting all levels of SOD1 maturation

Boyd

Calvo

Liu

et al. 2019

Journal of Biological Chemistry

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Edited by Ruma BanerjeeCopper (Cu) is essential for the survival of aerobic organisms through its interaction with molecular oxygen (O 2 ). However, Cu's chemical properties also make it toxic, requiring specific cellular mechanisms for Cu uptake and handling, mediated by Cu chaperones. CCS1, the budding yeast (S. cerevisiae) Cu chaperone for Cu-zinc (Zn) superoxide dismutase (SOD1) activates by directly promoting both Cu delivery and disulfide formation in SOD1. The complete mechanistic details of this transaction along with recently proposed molecular chaperone-like functions for CCS1 remain undefined. Here, we present combined structural, spectroscopic, kinetic, and thermodynamic data that suggest a multifunctional chaperoning role(s) for CCS1 during SOD1 activation. We observed that CCS1 preferentially binds a completely immature form of SOD1 and that the SOD1⅐CCS1 interaction promotes high-affinity Zn(II) binding in SOD1. Conserved aromatic residues within the CCS1 C-terminal domain are integral in these processes. Previously, we have shown that CCS1 delivers Cu(I) to an entry site at the SOD1⅐CCS1 interface upon binding. We show here that Cu(I) is transferred from CCS1 to the entry site and then to the SOD1 active site by a thermodynamically driven affinity gradient. We also noted that efficient transfer from the entry site to the active site is entirely dependent upon the oxidation of the conserved intrasubunit disulfide bond in SOD1. Our results herein provide a solid foundation for proposing a complete molecular mechanism for CCS1 activity and reclassification as a first-of-its-kind "dual chaperone."Copper (Cu) 2 is required for the activation of dioxygen, a function essential for the survival of aerobic organisms (1). Figure 4. Kinetic analysis of CCS1 mediated copper delivery to sites on SOD1. Stopped-flow kinetic traces at 260 nm and corresponding curve fittings (red line) obtained upon rapid mixing of Cu(I)-Ccs (20 M) with equal volumes of apo H46R/H48Q (X,Zn-SOD1 SH ) or WT E,Zn-SOD1 SH (20 M) under aerobic or anaerobic conditions are shown. The decreased absorbance at 260 nm (top left) corresponds to the copper ion moving from the cysteine coordination of CCS1 and/or SOD1 and entering the histidine coordination of the SOD1 active site. Increased absorbance at 260 nm shows the copper ion transfer from CCS1 cysteines to the SOD1⅐CCS1 2Cys/1His entry site.

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Section: Chaperoning Roles For Ccs1supporting

confidence: 92%

The yeast copper chaperone for copper-zinc superoxide dismutase (CCS1) is a multifunctional chaperone promoting all levels of SOD1 maturation

Boyd

Calvo

Liu

et al. 2019

Journal of Biological Chemistry

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“…Steric zipper structure of the segment KVWGSI suggests a weak role of this segment in full-length SOD1 fibrillation. Structural studies of SOD1 aggregates have been limited to structures of full-length mutants with or without metals bound, [28][29][30][31] which suggest that most mutations destabilize the native structure. However, these studies do not illustrate the structure of pathogenic SOD1 aggregates.…”

Section: Discussionmentioning

confidence: 99%

Atomic structures of corkscrew‐forming segments of SOD1 reveal varied oligomer conformations

et al. 2018

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The aggregation cascade of disease-related amyloidogenic proteins, terminating in insoluble amyloid fibrils, involves intermediate oligomeric states. The structural and biochemical details of these oligomers have been largely unknown. Here we report crystal structures of variants of the cytotoxic oligomer-forming segment residues 28-38 of the ALS-linked protein, SOD1. The crystal structures reveal three different architectures: corkscrew oligomeric structure, nontwisting curved sheet structure and a steric zipper proto-filament structure. Our work highlights the polymorphism of the segment 28-38 of SOD1 and identifies the molecular features of amyloidogenic entities.

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“…Activated immune cells, particularly macrophages, can produce ROS, which contributes to mitochondrial dysfunction and ultimately neuronal apoptosis. Superoxide dismutase (SOD) binds free superoxide radicals for conversion into molecular oxygen and hydrogen peroxide, the latter of which is then broken down by catalase (101). Over 160 mutations in the SOD gene have been found in forms of ALS (102,103).…”

Section: Downstream Inflammatory Mediators Of Neurodegenerationmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

398

240

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Insights into the Role of the Unusual Disulfide Bond in Copper-Zinc Superoxide Dismutase

Cited by 71 publications

References 58 publications

The yeast copper chaperone for copper-zinc superoxide dismutase (CCS1) is a multifunctional chaperone promoting all levels of SOD1 maturation

The yeast copper chaperone for copper-zinc superoxide dismutase (CCS1) is a multifunctional chaperone promoting all levels of SOD1 maturation

Atomic structures of corkscrew‐forming segments of SOD1 reveal varied oligomer conformations

CNS inflammation and neurodegeneration

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