A Leucine-to-Proline Substitution Causes a Defective α1-Antichymotrypsin Allele Associated with Familial Obstructive Lung Disease

Poller, Wolfgang; Faber, J.-P.; Weidinger, S.; Tief, K.; Scholz, Sonja W.; Fischer, M.; Olek, K.; Kirchgesser, Michael; Heidtmann, H.-H.

doi:10.1006/geno.1993.1396

Cited by 92 publications

(54 citation statements)

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“…1 Since the first structure of cleaved human a 1 -proteinase inhibitor, 2 X-ray and other structural studies of different serpins and serpins complexes have revealed remarkable similarities of secondary and tertiary structures for all serpins. In the metastable native conformation, serpins contain three antiparallel b-sheets (A, B, and C) and nine a-helices (1)(2)(3)(4)(5)(6)(7)(8)(9). b-sheet A is composed of five strands, while b-Sheets B and C are shorter and contained six and four strands, respectively.…”

Section: Introductionmentioning

confidence: 99%

Mutagenesis of the bovSERPINA3‐3 demonstrates the requirement of aspartate‐371 for intermolecular interaction and formation of dimers

Blanchet¹,

Péré-Brissaud²,

Duprat³

et al. 2012

Protein Science

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The family of serpins is known to fold into a metastable state that is required for the proteinase inhibition mechanism. One of the consequences of this conformational flexibility is the tendency of some mutated serpins to form polymers, which occur through the insertion of the reactive center loop of one serpin molecule into the A-sheet of another. This ''A-sheet polymerization'' has remained an attractive explanation for the molecular mechanism of serpinopathies. Polymerization of serpins can also take place in vitro under certain conditions (e.g., pH or temperature). Surprisingly, on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, bovSERPINA3-3 extracted from skeletal muscle or expressed in Escherichia coli was mainly observed as a homodimer. Here, in this report, by site-directed mutagenesis of recombinant bovSERPINA3-3, with substitution D371A, we demonstrate the importance of D371 for the intermolecular linkage observed in denaturing and reducing conditions. This residue influences the electrophoretic and conformational properties of bovSERPINA3-3. By structural modeling of mature bovSERPINA3-3, we propose a new ''non-A-sheet swap'' model of serpin homodimer in which D371 is involved at the molecular interface.

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Section: Introductionmentioning

confidence: 99%

Mutagenesis of the bovSERPINA3‐3 demonstrates the requirement of aspartate‐371 for intermolecular interaction and formation of dimers

Blanchet¹,

Péré-Brissaud²,

Duprat³

et al. 2012

Protein Science

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“…1a) allow the aberrant opening of the A-sheet, with the risk of the insertion, into its lower half, of the reactive loop of another molecule to give intermolecular linkage and polymerization of the serpin. Even minor changes in the shutter region of ␣ 1 -antitrypsin (8) and antichymotrypsin (9) result in their polymerization and intracellular aggregation with consequent lung and liver disease and similarly with C1-inhibitor (10) and antithrombin mutations (11) resulting in angioedema and thrombosis. But the best example of the critical function of this region comes from recent investigations of a novel form of familial neurodegenerative disease due to the aggregation within neurons of a brain-specific serpin, neuroserpin (12).…”

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confidence: 99%

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Zhou

Stein

Huntington

et al. 2003

Journal of Biological Chemistry

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Polymerization of serpins commonly results from mutations in the shutter region underlying the bifurcation of strands 3 and 5 of the A-sheet, with entry beyond this point being barred by a H-bond network centered on His-334. Exposure of this histidine in antithrombin, which has a partially opened sheet, allows polymerization and peptide insertion to occur at pH 6 or less when His-334 will be predictably protonated with disruption of the H-bond network. Similarly, thermal stability of antithrombin is pH-dependent with a single unfolding transition at pH 6, but there is no such transition when His-334 is buried by a fully closed A-sheet in heparincomplexed antithrombin or in ␣ 1 -antitrypsin. Replacement of His-334 in ␣ 1 -antitrypsin by a serine or alanine at pH 7.4 results in the same polymerization and looppeptide acceptance observed with antithrombin at low pH. The critical role of His-334 and the re-formation of its H-bond network by the conserved P8 threonine, on the full insertion of strand 4, are relevant for the design of therapeutic blocking agents. This is highlighted here by the crystallographic demonstration that glycerol, which at high concentrations blocks polymerization, can replace the P8 threonine and re-form the disrupted H-bond network with His-334.

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“…However the prevalence of the Pro 227 →Ala mutation may vary in different populations, since it was not detected in 102 Russian COPD patients [80]. A second amino acid substitution, Leu 55 →Pro, was reported by POLLER and co-workers [79] in three out of 200 unrelated COPD patients and none of 100 controls. Mean α 1 -ACT serum levels in the heterozygotes was 80% of normal, and the mutant protein had an altered pattern on isoelectric focusing and defective function.…”

Section: Alpha 1 -Antichymotrypsinmentioning

confidence: 95%

“…In cases where hereditary deficiency has been shown, transmission follows an autosomal dominant inheritance pattern [75,76]. No consistent clinical phenotype is associated with α 1 -ACT deficiency, although an increased prevalence has been reported in patients with childhood asthma [77] and COPD [78,79]. In two other studies, deficient patients had increased values of residual volume (RV) and of the RV/total lung capacity (TLC) ratio [75,76].…”

Section: Alpha 1 -Antichymotrypsinmentioning

confidence: 99%

Genetic risk factors for chronic obstructive pulmonary disease

Sandford¹,

Weir²,

Paré³

1997

Eur Respir J

193

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Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only a minority of cigarette smokers develop symptomatic disease. Studies of families and twins suggest that genetic factors also contribute to the development of COPD. We present a detailed literature review of the genes which have been investigated as potential risk factors for this disease.The only established genetic risk factor for COPD is homozygosity for the Z allele of the α 1 -antitrypsin gene. Heterozygotes for the Z allele may also be at increased risk. Other mutations affecting the structure of α 1 -antitrypsin or the regulation of gene expression have been identified as risk factors.Genes, including those for α 1 -antichymotrypsin, α 2 -macroglobulin, vitamin Dbinding protein and blood group antigens, have also been associated with the development of COPD. Variants of the cystic fibrosis transmembrane regulator gene have been identified as risk factors for disseminated bronchiectasis.The genetic basis to chronic obstructive pulmonary disease has begun to be elucidated and it is likely that several genes will be implicated in the pathogenesis of this disease. The knowledge gained from such studies may also prove relevant to other inflammatory diseases. Eur Respir J 1997; 10: 1380-1391. REVIEWChronic obstructive pulmonary disease (COPD) is characterized by decreased expiratory flow rates, increased pulmonary resistance and hyperinflation. The most important risk factor for the development of COPD is cigarette smoking [1]. Cigarette smoke, in combination with other factors, leads to two pathophysiological processes in the lung. The first is proteolytic destruction of the lung parenchyma, which increases the size of the airspaces; these eventually coalesce to form emphysematous spaces. The development of emphysema is associated with a loss of lung elastic recoil. The second process is inflammatory narrowing of peripheral airways, which is characterized by oedema, mucus hypersecretion and fibrosis, scarring, distortion and obliteration of peripheral airways. The loss of lung elastic recoil and the narrowing of the peripheral airways combine to decrease maximal expiratory flow from the lung and contribute to hyperinflation. In conjunction with gas exchange abnormalities, hyperinflation produces the symptoms of COPD.Despite the clear association of smoking and airway obstruction, there remains marked interindividual variation in the response to cigarette smoke. This indicates that there are additional genetic or environmental cofactors, which contribute to the development of COPD. It has been estimated that only 10-20% of chronic heavy smokers will ever develop symptomatic COPD [2,3]. Co-factors, such as childhood viral respiratory infections and environmental and occupational pollution, undoubtedly play a role in determining this susceptible subset. Furthermore, there is evidence that genetic susceptibility is of major importance. The epidemiological and clinical data that demonstrate a heredit...

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A Leucine-to-Proline Substitution Causes a Defective α1-Antichymotrypsin Allele Associated with Familial Obstructive Lung Disease

Cited by 92 publications

References 0 publications

Mutagenesis of the bovSERPINA3‐3 demonstrates the requirement of aspartate‐371 for intermolecular interaction and formation of dimers

Mutagenesis of the bovSERPINA3‐3 demonstrates the requirement of aspartate‐371 for intermolecular interaction and formation of dimers

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Genetic risk factors for chronic obstructive pulmonary disease

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