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An Alternative Mechanism of Bicarbonate-mediated Peroxidation by Copper-Zinc Superoxide Dismutase: RATES ENHANCED VIA PROPOSED ENZYME-ASSOCIATED PEROXYCARBONATE INTERMEDIATEmore
by Jennifer Elam and Joan S Valentine
Publication Date: 2003
Publication Name: Journal of Biological Chemistry
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Publication Date: 2003
Publication Name: Journal of Inorganic Biochemistry
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Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALSmore
by Jennifer Elam and Joan S Valentine
Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins,... more
Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed. Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery. Here we show that metal-deficient, pathogenic SOD1 mutant proteins crystallize in three different crystal forms, all of which reveal higher-order assemblies of aligned beta-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and beta-barrel elements of neighboring mutant SOD1 molecules. In all cases, non-native conformational changes permit a gain of interaction between dimers that leads to higher-order arrays. Normal beta-sheet-containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions. Loss of this protection through conformational rearrangement in the metal-deficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.
Publication Date: 2003
Publication Name: Nature Structural Biology
Research Interests: Water, Macromolecular X-Ray Crystallography, Transgenic Mice, Amyloid, Amyotrophic Lateral Sclerosis, and 16 moreHigher Order Thinking, Humans, Protein Crystallization, Mutation, Spinal Cord, Protein Aggregation, Superoxide Dismutase, Enzyme, Metals, Protein Secondary Structure Prediction, Protein Degradation, Protein Conformation, Protein Binding, Intermolecular Interaction, Conformational Change, and Autosomal Dominant(Higher Order Thinking, Humans, Protein Crystallization, Mutation, Spinal Cord, Protein Aggregation, Superoxide Dismutase, Enzyme, Metals, Protein Secondary Structure Prediction, Protein Degradation, Protein Conformation, Protein Binding, Intermolecular Interaction, Conformational Change, and Autosomal Dominant)
(Higher Order Thinking, Humans, Protein Crystallization, Mutation, Spinal Cord, Protein Aggregation, Superoxide Dismutase, Enzyme, Metals, Protein Secondary Structure Prediction, Protein Degradation, Protein Conformation, Protein Binding, Intermolecular Interaction, Conformational Change, and Autosomal Dominant)
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Variable Metallation of Human Superoxide Dismutase: Atomic Resolution Crystal Structures of Cu–Zn, Zn–Zn and As-isolated Wild-type Enzymesmore
by Joan S Valentine and Michael Hough
Publication Date: 2006
Publication Name: Journal of Molecular Biology
Research Interests: Molecular Biology, Macromolecular X-Ray Crystallography, Amyotrophic Lateral Sclerosis, Molecular, Crystal structure, and 12 moreHumans, Copper, Animals, Zinc, Superoxide Dismutase, Enzyme, Fine Structure Constant, Protein Conformation, Recombinant Proteins, Atomic Resolution, Biochemistry and cell biology, and Molecular Structure
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The Structure of Holo and Metal-deficient Wild-type Human Cu, Zn Superoxide Dismutase and its Relevance to Familial Amyotrophic Lateral Sclerosismore
by Michael Hough and Joan S Valentine
Publication Date: 2003
Publication Name: Journal of Molecular Biology
Research Interests: Molecular Biology, Macromolecular X-Ray Crystallography, Amyotrophic Lateral Sclerosis, Crystal structure, Humans, and 10 moreZinc, Superoxide Dismutase, Enzyme, Metals, Protein Secondary Structure Prediction, Protein Conformation, Structural Similarity Index, Binding Site, Biochemistry and cell biology, and Dimerization
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Publication Date: 2005
Publication Name: Protein Science
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. About 10% of ALS cases are inherited (familial), and a large subset of them are caused by mutations in the gene encoding... more
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. About 10% of ALS cases are inherited (familial), and a large subset of them are caused by mutations in the gene encoding the copper-zinc superoxide dismutase (SOD1). The detection of SOD1-positive inclusions in familial ALS patients suggests the role of SOD1 aggregation underlying the pathology of familial ALS. Although SOD1 mutant proteins are different in structure, stability and activity, they all exhibit a higher aggregation propensity than wild-type SOD1. We here review the recent studies on the role of metallation states and disulfide status in the unfolding, misfolding, and aggregation of SOD1. Investigations of the mechanism of SOD1 aggregation enhance our understanding of onset and progression of ALS and have implications for therapeutic approaches for treating ALS.
Publication Date: 2013
Publication Name: Current Topics in Medicinal Chemistry
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Publication Date: 2008
Publication Name: Proceedings of the National Academy of Sciences
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Publication Date: 2007
Publication Name: Proceedings of the National Academy of Sciences
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Uclacyanins, stellacyanins, and plantacyanins are distinct subfamilies of phytocyanins: Plant-specific mononuclear blue copper proteinsmore
by Chad Immoos and Joan S Valentine
The cDNAs encoding plantacyanin from spinach were isolated and characterized. In addition, four new cDNA sequences from Arabidopsis ESTs were identified that encode polypeptides resembling phytocyanins, plant-specific proteins... more
The cDNAs encoding plantacyanin from spinach were isolated and characterized. In addition, four new cDNA sequences from Arabidopsis ESTs were identified that encode polypeptides resembling phytocyanins, plant-specific proteins constituting a distinct family of mononuclear blue copper proteins. One of them encodes plantacyanin from Arabidopsis, while three others, designated as uclacyanin 1, 2, and 3, encode protein precursors that are closely related to precursors of stellacyanins and a blue copper protein from pea pods. Comparative analyses with known phytocyanins allow further classification of these proteins into three distinct subfamilies designated as uclacyanins, stellacyanins, and plantacyanins. This specification is based on (1) their spectroscopic properties, (2) their glycosylation state, (3) the domain organization of their precursors, and (4) their copper-binding amino acids. The recombinant copper binding domain of Arabidopsis uclacyanin 1 was expressed, purified, and shown to bind a copper atom in a fashion known as "blue" or type 1. The mutant of cucumber stellacyanin in which the glutamine axial ligand was substituted by a methionine (Q99M) was purified and shown to possess spectroscopic properties similar to uclacyanin 1 rather than to plantacyanins. Its redox potential was determined by cyclic voltammetry to be +420 mV, a value that is significantly higher than that determined for the wild-type protein (+260 mV). The available structural data suggest that stellacyanins (and possibly other phytocyanins) might not be diffusible electron-transfer proteins participating in long-range electron-transfer processes. Conceivably, they are involved in redox reactions occurring during primary defense responses in plants and/or in lignin formation.
Publication Date: 1998
Publication Name: Protein Science
Research Interests: Electrochemistry, Kinetics, Protein Science, Protein, Sequence alignment, and 11 moreCopper, Spectrophotometry, Arabidopsis, Metalloproteins, Molecular cloning, Protein Secondary Structure Prediction, Amino Acid Sequence, Base Sequence, PLANT PROTEINS, Oxidation-Reduction, and Biochemistry and cell biology
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The structure and unfolding of metal-free (apo) human wild-type SOD1 and three pathogenic variants of SOD1 (A4V, G93R, and H48Q) that cause familial amyotrophic lateral sclerosis have been studied with amide hydrogen/deuterium exchange... more
The structure and unfolding of metal-free (apo) human wild-type SOD1 and three pathogenic variants of SOD1 (A4V, G93R, and H48Q) that cause familial amyotrophic lateral sclerosis have been studied with amide hydrogen/deuterium exchange and mass spectrometry. The results indicate that a significant proportion of each of these proteins exists in solution in a conformation in which some strands of the beta-barrel (i.e. beta2) are well protected from exchange at physiological temperature (37 degrees C), whereas other strands (i.e. beta3 and beta4) appear to be unprotected from hydrogen/deuterium exchange. Moreover, the thermal unfolding of these proteins does not result in the uniform incorporation of deuterium throughout the polypeptide but involves the local unfolding of different residues at different temperatures. Some regions of the proteins (i.e. the "Greek key" loop, residues 104-116) unfold at a significantly higher temperature than other regions (i.e. beta3 and beta4, residues 21-53). Together, these results show that human wild-type apo-SOD1 and variants have a partially unfolded beta-barrel at physiological temperature and unfold non-cooperatively.
Publication Date: 2009
Publication Name: Journal of Biological Chemistry
Research Interests: Protein Folding, Mass Spectrometry, Biological Chemistry, Macromolecular X-Ray Crystallography, Amyotrophic Lateral Sclerosis, and 12 moreBiological Sciences, Humans, Biological, Temperature, Peptides, Superoxide Dismutase, Metals, CHEMICAL SCIENCES, Protein Secondary Structure Prediction, Molecular Conformation, Protein Conformation, and Protein Denaturation
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Publication Date: 2011
Publication Name: Journal of Biological Chemistry
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Hydrogen exchange monitored by mass spectrometry has been used to study the structural behavior of the pathogenic A4V variant of superoxide dismutase 1 (SOD1) in the metal-free (apo) form. Mass spectrometric data revealed that in the... more
Hydrogen exchange monitored by mass spectrometry has been used to study the structural behavior of the pathogenic A4V variant of superoxide dismutase 1 (SOD1) in the metal-free (apo) form. Mass spectrometric data revealed that in the disulfide-intact (S-S) form, the A4V variant is destabilized at residues 50-53, in the disulfide subloop of the dimer interface, but many other regions of the A4V protein exhibited hydrogen exchange properties identical to that of the wild type protein. Additionally, mass spectrometry revealed that A4V apoSOD1(S-S) undergoes slow localized unfolding in a large segment of the beta-barrel that included beta3, beta4, and loops II and III. In the disulfide-reduced form, A4V apoSOD1 exchanged like a "random coil" polypeptide at 20 degrees C and began to populate folded states at 4 degrees C. These local and global unfolding events could facilitate intermolecular protein-protein interactions that cause the aggregation or neurotoxicity of A4V SOD1.
Publication Date: 2006
Publication Name: Journal of Biological Chemistry
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High resolution structures of wild type and apo human CuZn superoxide dismutase and its fals-related mutantsmore
by Michael Hough and Joan S Valentine
Publication Date: 2002
Publication Name: Acta Crystallographica Section A Foundations of Crystallography
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Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutantsmore
by Michael Hough and Joan S Valentine
Publication Date: 2004
Publication Name: Proceedings of the National Academy of Sciences
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Differential scanning calorimetry of copper-zinc-superoxide dismutase, the apoprotein, and its zinc-substituted derivativesmore
by Luis A Marky and Joan S Valentine
Publication Date: 1988
Publication Name: Biochemistry
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ABSTRACT The long-lived transient complexes (2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene)(H2O)- Co-III-OOR2+, [(tim)(H2O)Co-III-O2R](2+) (R = CH2OH, CH2CN, CCl3) were prepared from the reaction of... more
ABSTRACT The long-lived transient complexes (2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene)(H2O)- Co-III-OOR2+, [(tim)(H2O)Co-III-O2R](2+) (R = CH2OH, CH2CN, CCl3) were prepared from the reaction of [Co-II(tim)(H2O)(2)](2+) with the corresponding peroxyl radicals, applying radiation chemistry techniques. The resultant transient complexes, which are relatively stable (lifetime of days), were subsequently treated with methylperoxyl (CH3O2.) radicals to form [Co-III(tim)(H2O)(2)](3+) and formaldehyde. The results point out that the CH3O2 radicals rapidly oxidize MOOR peroxides.
Publication Date: 2002
Publication Name: European Journal of Inorganic Chemistry
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by Troy Stich and Joan S Valentine
Publication Date: 2010
Publication Name: Journal of the American Chemical Society
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Comparison of Two Yeast MnSODs: Mitochondrial Saccharomyces cerevisiae versus Cytosolic Candida albicansmore
by Troy Stich and Joan S Valentine