Oxidation of either methionine super351 or methionine super358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity

Taggart, Clifford C.; Cervantes-Laurean, Daniel; Kim, Geumsoo; McElvaney, Noel G.; Wehr, Nancy B.; Moss, Joel; Levine, Rodney L.

doi:10.1074/jbc.m004850200

Cited by 185 publications

(178 citation statements)

References 47 publications

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“…The detrimental effects of CS on the lung synergize with those of A1AT deficiency, leading to severe, earlier onset of emphysema. In addition, CS oxidizes the Met358 within the RCL, which diminishes the antielastase function of the protein (8). We have shown previously that preincubation of A1AT with CS extract or hydrogen peroxide diminishes the serpin′s ability to inhibit caspase-3 activity against a fluorescently tagged substrate (3), but the CS effect on the protein-protein interaction between A1AT and caspase-3 has not been tested.…”

Section: Effect Of Cigarette Smoke Exposure and Structural Modificatimentioning

confidence: 99%

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Lockett

Demark

et al. 2012

Mol Med

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α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.

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Section: Effect Of Cigarette Smoke Exposure and Structural Modificatimentioning

confidence: 99%

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Lockett

Demark

et al. 2012

Mol Med

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“…The importance of α1AT and NE in lung protection and destruction respectively is illustrated by α1AT deficiency, a hereditary disorder associated with polymerisation of the mutant α1AT in the liver, decreased secretion of α1AT into the circulation and a markedly diminished anti-NE protective defence in the lung [67]. This condition is associated with premature aggressive emphysema, a condition which is aggravated greatly by the effects of cigarette smoke in oxidising and further inactivating α1AT leading to an unopposed action of NE [68].…”

Section: Anti-ne Defences Of the Lungmentioning

confidence: 99%

Targeting neutrophil elastase in cystic fibrosis

Kelly

Greene

McElvaney

2008

Expert Opinion on Therapeutic Targets

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“…Oxidation of either methionine 351 or 358 in the binding site of α 1 -antitrypsin destroys the its ability to bind to and inhibit elastase (39). This mechanism appear to play a significant role in linking tobacco smoking to lung emphysema and chronic obstructive pulmonary disease (40).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

Ross¹,

MacLeod

Plaxco

et al. 2008

Radiation Research

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Background-Normal tissue radiation injury is associated with loss of vascular thromboresistance, notably because of deficient levels of endothelial thrombomodulin (TM). TM is located on the luminal surface of most endothelial cells and serves critical anticoagulant and anti-inflammatory functions. Chemical oxidation of a specific methionine residue (Met388) at the thrombin-binding site in TM reduces its main functional activity, i.e., the ability to activate protein C. We examined whether exposure to ionizing radiation affects TM in a similar manner.

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Oxidation of either methionine super351 or methionine super358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity

Cited by 185 publications

References 47 publications

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Targeting neutrophil elastase in cystic fibrosis

Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

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