Furin Proteolytically Processes the Heparin-binding Region of Extracellular Superoxide Dismutase

Bowler, Russell P.; Nicks, Michael; Olsen, Dorte Aalund; Thøgersen, Ida B.; Valnickova, Zuzana; Højrup, Peter; Franzusoff, Alex; Enghild, Jan J.; Crapo, James D.

doi:10.1074/jbc.m105409200

Cited by 61 publications

(38 citation statements)

References 42 publications

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“…This has been confirmed by another cross-sectional study [18]. The underlying mechanism of these associations may be explained by reduced proteolytic processing of mutated SOD3 protein [37] and a higher SOD3 level in blood plasma due to lower affinity to heparan sulphate in the extracellular matrix [20,38]. The present authors additionally found that the protective effect of this SNP on longitudinal FEV1 change appears in neversmokers.…”

Section: Sod Genetics In Copd and Bhr M Siedlinski Et Alsupporting

confidence: 74%

Superoxide dismutases, lung function and bronchial responsiveness in a general population

Siedliński¹,

Diemen

Postma

et al. 2009

European Respiratory Journal

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Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD). Superoxide dismutases (SODs) can prevent an increase in oxidative burden.A total of 1,390 subjects from the prospective Vlagtwedde-Vlaardingen cohort were genotyped for two single nucleotide polymorphisms (SNPs) in SOD2 and four SNPs in SOD3, which were further analysed for associations with the presence of bronchial hyperresponsiveness (BHR; provocative concentration causing a 10% fall in the forced expiratory volume in one second (FEV1; PC10 f8 mg?mL -1 of histamine), COPD (defined as Global Initiative for Chronic Obstructive Lung Disease stage II or higher), lung function level and the longitudinal course of FEV1.The intronic C5774T SNP of SOD2 was significantly associated with the presence of COPD and BHR in the total population. The T/T genotype for this polymorphism and the Val/Val genotype for the SOD2 Ala16Val substitution were risk factors for BHR in individuals without COPD. The SOD3 Arg213Gly substitution was associated with slower FEV1 decline in never-smokers exclusively, and the SOD3 G(-4466)T SNP was associated with a lower vital capacity level.Both SOD2 polymorphisms are associated with bronchial hyperresponsiveness, a risk factor for chronic obstructive pulmonary disease, while SOD2 C5774T additionally confers a risk for chronic obstructive pulmonary disease in the total population. The current authors furthermore confirm previously reported associations of SOD3 single nucleotide polymorphisms with lung function in the general population.

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Section: Sod Genetics In Copd and Bhr M Siedlinski Et Alsupporting

confidence: 74%

Superoxide dismutases, lung function and bronchial responsiveness in a general population

Siedliński¹,

Diemen

Postma

et al. 2009

European Respiratory Journal

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“…15 The mechanism by which the 213Gly variant confers this protection comes from studies showing it alters the heparin binding site of the SOD3 protein reducing its affinity for the extracellular matrix and increasing its half life by reducing normal proteolytic cleavage. 17 It has been proposed that the secretion of uncleaved SOD3 (generated by the 213Gly variant) may result in a greater availability of SOD3 to provide an antioxidant or anti-inflammatory response. 17 22 However, it should be noted that a deleterious effect by reducing bound SOD3 to extracellular matrix has also been suggested.…”

Section: Discussionmentioning

confidence: 99%

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function

Young

Black

Eddy

et al. 2006

Respiratory Medicine: COPD Update

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Background: Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function. Methods: In a case-control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD. Results: Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested. Conclusions: The 213Gly variant of the SOD3 gene may, through antioxidant or anti-inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.

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“…The N-terminal region of EC-SOD is important for the formation of tetramers (8)(9)(10), and the C-terminal region (Val-194-Ala-222) encompasses a heparinbinding region, which is responsible for the immobilization of EC-SOD in the extracellular matrix (11,12). The heparinbinding region of EC-SOD can be removed by an intracellular proteolytic event before secretion (13,14). Consequently, EC-SOD tetramers with no (type A), intermediate (type B), or high (type C) affinity for the extracellular matrix are produced (11,12).…”

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confidence: 99%

The dual nature of human extracellular superoxide dismutase: One sequence and two structures

Petersen

Oury

Valnickova

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Human extracellular superoxide dismutase (EC-SOD; EC 1.15.1.1) is a scavenger of superoxide anions in the extracellular space. The amino acid sequence is homologous to the intracellular counterpart, Cu͞Zn superoxide dismutase (Cu͞Zn-SOD), apart from N-and C-terminal extensions. Cu͞Zn-SOD is a homodimer containing four cysteine residues within each subunit, and EC-SOD is a tetramer composed of two disulfide-bonded dimers in which each subunit contains six cysteines. The amino acid sequences of all EC-SOD subunits are identical. It is known that Cys-219 is involved in an interchain disulfide. To account for the remaining five cysteine residues we purified human EC-SOD and determined the disulfide bridge pattern. The results show that human EC-SOD exists in two forms, each with a unique disulfide bridge pattern. One form (active EC-SOD) is enzymatically active and contains a disulfide bridge pattern similar to Cu͞Zn-SOD. The other form (inactive EC-SOD) has a different disulfide bridge pattern and is enzymatically inactive. The EC-SOD polypeptide chain apparently folds in two different ways, most likely resulting in different three-dimensional structures. Our study shows that one gene may produce proteins with different disulfide bridge arrangements and, thus, by definition, different primary structures. This observation adds another dimension to the functional annotation of the proteome. T wo isoforms of Cu͞Zn-containing superoxide dismutase (SOD) enzymes exist in mammals (1, 2). Cu͞Zn-SOD is found in the intracellular space, and extracellular SOD (EC-SOD) predominantly is found in the extracellular matrix of most tissues (3). Both enzymes dismutate the superoxide anion into hydrogen peroxide and oxygen with diffusion-limited rate constants (Ͼ10 9 M Ϫ1 sec Ϫ1 ), and both are inhibited by cyanide and azide (4, 5). Human Cu͞Zn-SOD is a homodimer with a molecular mass of 32 kDa, and human EC-SOD is a tetramer of Ϸ135 kDa (4). The subunit of each isoform contains one Cu(II) and one Zn(II) atom. The central region of EC-SOD (His-96 to ) is homologous to human Cu͞Zn-SOD and contains all of the ligands essential for the coordination of the active site Cu(II) and Zn(II) ions (6, 7). The N-terminal region of EC-SOD is important for the formation of tetramers (8-10), and the C-terminal region ) encompasses a heparinbinding region, which is responsible for the immobilization of EC-SOD in the extracellular matrix (11, 12). The heparinbinding region of EC-SOD can be removed by an intracellular proteolytic event before secretion (13,14). Consequently, EC-SOD tetramers with no (type A), intermediate (type B), or high (type C) affinity for the extracellular matrix are produced (11,12). These tetramers are composed of cleaved polypeptides (type A), intact polypeptides (type C), or a mixture (type B). In addition, the C-terminal region supports the formation of disulfide-linked dimers via 16).The x-ray structure of Cu͞Zn-SOD shows that the active-site channel is maintained by an intrapolypeptide disulfide bond between two highly co...

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Furin Proteolytically Processes the Heparin-binding Region of Extracellular Superoxide Dismutase

Abstract: Extracellular superoxide dismutase (EC-SOD

Cited by 61 publications

References 42 publications

Superoxide dismutases, lung function and bronchial responsiveness in a general population

Superoxide dismutases, lung function and bronchial responsiveness in a general population

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function

The dual nature of human extracellular superoxide dismutase: One sequence and two structures

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