Superoxide-Dependent Peroxidase Activity of H48Q: A Superoxide Dismutase Variant Associated with Familial Amyotrophic Lateral Sclerosis

Liochev, Stefan I.; Chen, Li Li; Hallewell, Robert A.; Fridovich, Irwin

doi:10.1006/abbi.1997.0298

Cited by 44 publications

(31 citation statements)

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“…H48Q mutant is consistent with what is observed in two different crystal structures of singly substituted H46R SOD1 that reside in the protein data bank, which contains a combined total of twelve H46R SOD1 subunits (19,20). In each case, the side chain of Arg-46 in these subunits donates a hydrogen bond to an acceptor across the active site channel.…”

Section: Discussionsupporting

confidence: 86%

“…These hydrogen bond acceptors include the indole nitrogen of His-63, the carbonyl or side-chain oxygen of Thr-137 (as in Fig. 1), or a sidechain oxygen of Asp-124 (19,20). Taken together, these data suggest that the H46R substitution alone markedly disrupts the binding of copper in the copper site.…”

Section: Discussionmentioning

confidence: 85%

“…In contrast, the singly substituted human H48Q SOD1 protein has been shown to bind copper ions at the copper site when expressed in the presence of high levels of copper (38) or when re-folded in vitro (20). Spectroscopic analysis of SOD1-H48Q, expressed in insect cells grown in media supplemented with copper and zinc sulfate (up to 300 M), suggested that the copper is coordinated in a geometry that deviates from the distorted tetragonal arrangement found in wild-type toward one that is more regular (38).…”

Section: Discussionmentioning

confidence: 96%

“…Additional substitutions at the two other copper ligands (His-63 to Gly and His-120 to Gly), eliminate the copper-binding ligands, generating a protein that remains capable of inducing motor neuron disease in transgenic mice (17). Studies of SOD1-H46R suggest that this single mutation interferes with copper binding (18,19), whereas the H48Q mutant can be made to bind copper in the correct site, although with an altered coordination geometry (20). The copper-binding abilities of H46R/H48Q or SOD1-Quad are also predicted to be severely compromised, but this has not yet been demonstrated experimentally.…”

mentioning

confidence: 99%

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Disease-associated Mutations at Copper Ligand Histidine Residues of Superoxide Dismutase 1 Diminish the Binding of Copper and Compromise Dimer Stability

Wang

Caruano-Yzermans

Rodriguez

et al. 2007

Journal of Biological Chemistry

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A subset of superoxide dismutase 1 (Cu/Zn-SOD1) mutants that cause familial amyotrophic lateral sclerosis (FALS) have heightened reactivity with ؊ ONOO and H 2 O 2 in vitro. This reactivity requires a copper ion bound in the active site and is a suggested mechanism of motor neuron injury. However, we have found that transgenic mice that express SOD1-H46R/ H48Q, which combines natural FALS mutations at ligands for copper and which is inactive, develop motor neuron disease. Using a direct radioactive copper incorporation assay in transfected cells and the established tools of single crystal x-ray diffraction, we now demonstrate that this variant does not stably bind copper. We find that single mutations at copper ligands, including H46R, H48Q, and a quadruple mutant H46R/H48Q/ H63G/H120G, also diminish the binding of radioactive copper. Further, using native polyacrylamide gel electrophoresis and a yeast two-hybrid assay, the binding of copper was found to be related to the formation of the stable dimeric enzyme. Collectively, our data demonstrate a relationship between copper and assembly of SOD1 into stable dimers and also define diseasecausing SOD1 mutants that are unlikely to robustly produce toxic radicals via copper-mediated chemistry. Amyotrophic lateral sclerosis (ALS),3 which is characterized by progressive muscle weakness and motor neuron loss, presents as both sporadic and familial (FALS) illness. A subset of FALS cases is caused by missense mutations in the superoxide scavenging enzyme, Cu/Zn-superoxide dismutase 1 (SOD1) (1, 2). To date, over 100 different point mutations, and Ͼ5 early termination mutations have been linked to FALS (www. alsod.org) (for reviews see Refs. 2-4). Early studies of FALS-SOD1 enzymes demonstrated that some mutants retain high levels of activity and relatively long half lives (5). Moreover, mutant proteins that are inactive or short-lived do not exhibit evidence of dominant negative action with regard to the superoxide-scavenging activity of enzyme derived from the normal allele (6). In transgenic mice, the hyperexpression of the G93A and G37R variants of FALS-SOD1 increases superoxide scavenging activity, kills motor neurons, and causes paralysis (7,8). SOD1 knock-out mice do not develop ALS-like phenotypes but do show sensory and motor neuropathy (9). Together, these studies establish that SOD1 mutations cause ALS through a gained toxic property. Although expressed ubiquitously (8, 10), mutant SOD1 selectively damages motor neurons, by mechanisms yet to be fully understood.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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Disease-associated Mutations at Copper Ligand Histidine Residues of Superoxide Dismutase 1 Diminish the Binding of Copper and Compromise Dimer Stability

Wang

Caruano-Yzermans

Rodriguez

et al. 2007

Journal of Biological Chemistry

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“…The outcomes from this activity are manifold. In some cases, peroxidase activity can generate superoxide from H 2 O 2 , and a hydroxyl radical that modifies the imidazole ring of histidine, which irreversibly inactivates the enzyme (33,34). If cellular conditions favor it, H 2 O 2 can react with carbonate to form peroxymonocarbonate, which can also be processed by the enzyme to create the carbonate radical (4,37,70).…”

Section: Figmentioning

confidence: 99%

Regulation of CuZnSOD and Its Redox Signaling Potential: Implications for Amyotrophic Lateral Sclerosis

Hitchler

Domann

2014

Antioxidants & Redox Signaling

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Significance: Molecular oxygen is a Janus-faced electron acceptor for biological systems, serving as a reductant for respiration, or as the genesis for oxygen-derived free radicals that damage macromolecules. Superoxide is well known to perturb nonheme iron proteins, including Fe/S proteins such as aconitase and succinate dehydrogenase, as well as other enzymes containing labile iron such as the prolyl hydroxylase domain-containing family of enzymes; whereas hydrogen peroxide is more specific for two-electron reactions with thiols on glutathione, glutaredoxin, thioredoxin, and the peroxiredoxins. Recent Advances: Over the past two decades, familial cases of amyotrophic lateral sclerosis (ALS) have been shown to have an association with commonly altered superoxide dismutase 1 (SOD1) activity, expression, and protein structure. This has led to speculation that an altered redox balance may have a role in creating the ALS phenotype. Critical Issues: While SOD1 alterations in familial ALS are manifold, they generally create perturbations in the flux of electrons. The nexus of SOD1 between one-and two-electron signaling processes places it at a key signaling regulatory checkpoint for governing cellular responses to physiological and environmental cues. Future Directions: The manner in which ALS-associated mutations adjust SOD1's role in controlling the flow of electrons between one-and two-electron signaling processes remains obscure. Here, we discuss the ways in which SOD1 mutations influence the form and function of copper zinc SOD, the consequences of these alterations on free radical biology, and how these alterations might influence cell signaling during the onset of ALS. Antioxid. Redox Signal. 20, 1590Signal. 20, -1598

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Zinc: The brain's dark horse

Bitanihirwe

Cunningham

2009

Synapse

240

154

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Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.

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Superoxide-Dependent Peroxidase Activity of H48Q: A Superoxide Dismutase Variant Associated with Familial Amyotrophic Lateral Sclerosis

Cited by 44 publications

References 0 publications

Disease-associated Mutations at Copper Ligand Histidine Residues of Superoxide Dismutase 1 Diminish the Binding of Copper and Compromise Dimer Stability

Disease-associated Mutations at Copper Ligand Histidine Residues of Superoxide Dismutase 1 Diminish the Binding of Copper and Compromise Dimer Stability

Regulation of CuZnSOD and Its Redox Signaling Potential: Implications for Amyotrophic Lateral Sclerosis

Zinc: The brain's dark horse

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