Oxygen-dependent activation of Cu,Zn-superoxide dismutase-1

Fetherolf, Morgan M.; Boyd, Stefanie D.; Winkler, Duane D.; Winge, Dennis R.

doi:10.1039/c6mt00298f

Cited by 40 publications

(75 citation statements)

References 132 publications

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“…It has been generally assumed that SOD1 diffusively acquires Zn from the available pool within the cell as the first step in its maturation process (reviewed in Ref. 13). This is supported by the lack of Zn-specific metallo-chaperones that have been discovered, to date, and the fact that WT SOD1 purified from yeast lackingCCS1isdevoidofCu,yetenrichedwithZn(Ͼ1Zn/monomer) (25).…”

Section: Discussionmentioning

confidence: 99%

“…Without CCS1 present, the population of SOD1 disintegrates into an assorted collection of improperly metallated molecules ranging from completely Zn-free to conformers with 2 Zn ions/monomer (reviewed in Ref. 13)). CCS1 likely plays an all-encompassing faciliatory role during SOD1 activation that starts with guaranteeing "correct" Zn status of the SOD1 molecule.…”

Section: Discussionmentioning

confidence: 99%

“…Newly translated SOD1 is monomeric and inactive (10 -12), and conversion to the active homodimer only occurs after several posttranslational modifications (reviewed in Ref. 13). The Cu chaperone for SOD1 (CCS1) mediates at least two of these modifications (14) by engaging nascent SOD1, inserting a Cu ion, and directing disulfide bond formation (15,16).…”

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confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Radiation is known to increase the production of reactive ROS that induces oxidative damage, and SOD plays an important role in alleviating oxidative stress. However, to the best of our knowledge, no one has studied whether oxidative stress is involved in the development of ORN. Interestingly, we found that increased oxidative stress induced by radiation was significantly attenuated by α2M, suggesting that antioxidation might play some role in the beneficial effects of α2M on ORN during the acute phase after radiation.…”

Section: Discussionmentioning

confidence: 99%

Protective role of α2‐macroglobulin against jaw osteoradionecrosis in a preclinical rat model

Kong

Chen

et al. 2018

J Oral Pathology Medicine

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Objective We have previously demonstrated the effect of alpha‐2‐macroglobulin (α2M) in the remediation of radiation‐induced cellular damage. Here, we investigated the protective effects of α2M in a preclinical rat model of jaw osteoradionecrosis (ORN). Methods Eighteen rats were divided randomly into three groups: the control group, the radiation therapy (RT) alone group, and the radiated mandibles pretreated with α2M (α2M + RT) group. One month after radiation, all left molar teeth were extracted. After another 3 months, the animals were sacrificed and body weight, histopathology, microcomputed tomography and immunofluorescence were evaluated in all groups. Results The RT group showed serious alopecia, bone exposure, inflammation, necrosis, fibrosis, and the absence of new bone formation within the socket. The α2M + RT group exhibited less alopecia than the RT group and slight inflammation and fibrosis in the bone marrow cavity. The cortical bone was similar to normal bone tissue. Interestingly, compared with RT group, serum superoxide dismutase levels in the α2M + RT group increased at the 1th day (P = 0.037), 14th day (P = 0.012), while reactive oxygen species levels clearly decreased at the 1th day (P< 0.001), 14th day (P = 0.007), and 28th day (P = 0.013). Conclusions A clinically translational model of jaw ORN was successfully established and the application of α2M prior to radiation protected the bone from being injured by the radiation, possibly related to oxidative stress.

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“…62 SOD1 maturation in both the cytosol and the IMS requires the copper chaperone for SOD1 (CCS), which inserts copper into apo-SOD1 and catalyzes the formation of an intermolecular disulphide bond that stabilizes the homodimer and is essential for enzyme activity. 63, 64 The relative distribution of CCS between the cytosol and the mitochondrion is governed by the MIA40-ERV1 disulphide relay system, which oxidizes two cysteines within its first domain to form a disulphide bond that promotes CCS retention within the IMS. 65 Since both SOD1 and CCS are imported into the IMS as apo-proteins, the copper required for the maturation and catalytic activity of SOD1 must also come from the matrix copper pool.…”

Section: Copper In Mitochondriamentioning

confidence: 99%

The mitochondrion: a central architect of copper homeostasis

2017

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All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.

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Oxygen-dependent activation of Cu,Zn-superoxide dismutase-1

Cited by 40 publications

References 132 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

Protective role of α2‐macroglobulin against jaw osteoradionecrosis in a preclinical rat model

The mitochondrion: a central architect of copper homeostasis

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