• Journal of Microbiology
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• v.41 no.4
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• pp.335-339
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• 2003

Many genetic variants of ${\alpha}_1$-antitrypsin have been associated with early onset emphysema and liver cirrhosis. However, the detailed structural basis of pathogenic ${\alpha}_1$-antitrypsin molecules is rarely known. Here we found that a recombinant $M_{malton}$ variant (Phe52-deleted) lost inhibitory activity by spontaneous conformational conversion into a more stable, inactive form under physiological conditions. Biochemical and spectroscopic data suggested that the variant converts into a reactive center loop-inserted conformation, resembling the latent form of plasminogen activator inhibitor-1.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.23 no.2
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• pp.146-153
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• 2020

Purpose: Alpha-1 antitrypsin deficiency (A1ATD) in one of the most common genetic causes of liver disease in children. We aimed to analyze the clinical characteristics and outcomes of patients with A1ATD. Methods: This study included patients with A1ATD from five pediatric hepatology units. Demographics, clinical findings, genetics, and outcome of the patients were recorded (n=25). Results: Eight patients (32.0%) had homozygous PiZZ genotype while 17 (68.0%) had heterozygous genotype. Patients with PiZZ genotype had lower alpha-1 antitrypsin levels than patients with PiMZ genotype (37.6±7.7 mg/dL vs. 66.5±22.7 mg/dL, p=0.0001). Patients with PiZZ genotype were diagnosed earlier than patients with PiMZ genotype, but this was not significant (13±6.8 months vs. 23.7±30.1 months, p=0.192). Follow-up revealed the death of one patient (12.5%) with a homozygous mutation, and revealed that one patient had child A cirrhosis, five patients (62.5%) had chronic hepatitis, and one patient (12.5%) was asymptomatic. Nine of the 17 patients with a heterozygous mutation had chronic hepatitis (52.9%), two (11.7%) had child A cirrhosis, and six (35.2%) were asymptomatic. Overall, 18 (72%) of the 25 children had liver pathology in the long-term. Conclusion: Although prevalence is rare, patients with liver disorders should be checked for alpha-1 antitrypsin levels. Moreover, long-term follow-up is essential because most patients have a liver pathology.

• Proceedings of the Korean Biophysical Society Conference
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• 2001.06a
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• pp.31-31
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• 2001

The native strain of serpins (serine protease inhibitors) has been recognized as a mechanism of biological regulation. Indeed, some stabilizing single residue mutations of human $\alpha$$_1$-antitrypsin, a prototype serpin, relieved local strain and caused the loss of inhibitory activity. The native strain of $\alpha$$_1$-antitrypsin is distributed throughout the whole molecule, but the strain that regulates the function directly is highly localized in the regions that appear to be mobilized during complex formation with a target protease.(omitted)

• Proceedings of the Korean Biophysical Society Conference
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• 1997.07a
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• pp.40-40
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• 1997

$\alpha$$_1$- Antitrypsin is a key plasma serine protease inhibitor and its prime physiological role is an inhibitor of leukocyte elastase. The reactive center loop of $\alpha$$_1$-antitrypsin is characterized by the unusual mobility and the ability of insertion into the central $\beta$ sheet A. In particular the rate of loop insertion is considered to be critical for the formation of a stable complex between a serpin and its target protease.(omitted)

• Proceedings of the Korean Biophysical Society Conference
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• 1998.06a
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• pp.24-24
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• 1998

The effect of stabilizing single ammo acid replacements at the sites of Phe 51, Ala 70, and Met 374 on the folding of $\alpha$$_1$-antitrypsin was investigated by fluorescence spectroscopy. The residues Phe 51 and Met 374 are located in the hydrophobic core of the molecule, B $\beta$-sheet.(omitted)

• Proceedings of the Korean Biophysical Society Conference
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• 1996.07a
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• pp.14-14
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• 1996

The metastable native state of proteins plays an important role in regulating biological functions. The native strain of serpins (serine protease inhibitors) are considered to be crucial for the inhibitory function. Several thermostable mutations of human $\alpha$$_1$-antitrypsin, a prototype inhibitory serpin, were identified in a systematic search targeted at the hydrophobic core of the molecule [Nature structural biology, vol. 3, no. 6, 497-500(1996)]. (omitted)

• Proceedings of the Korean Biophysical Society Conference
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• 1999.06a
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• pp.41-41
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• 1999

The native forms of some proteins such as inhibitory serpins (serine protease inhibitors) and viral membrane fusion proteins are metastable, which is critical to their functions. To understand the mechanism of how native metastability regulates the inhibitory function of serpins, we characterized stabilizing mutations of $\alpha$$_1$-antitrypsin, a prototype serpin, in which Gly 117 was replaced by a series of larger hydrophobic residues.(omitted)

• Proceedings of the Korean Biophysical Society Conference
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• 1997.07a
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• pp.39-39
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• 1997

Native strain of inhibitory SERPINS (Serine protease inhibitors) is thought to be used in the facile conformational switch to play biological regulation. Many heat stable variants of $\alpha$$_1$-antitrypsin, a prototype of inhibitory serpins, increased their stability by reducing the native strain.(omitted)

• Bulletin of the Korean Chemical Society
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• v.35 no.9
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• pp.2781-2786
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• 2014

Human ${\alpha}_1$-antitrypsin (${\alpha}_1$-AT) is a natural inhibitor of neutrophil elastases and has several dozens of genetic variants. Most of the deficient genetic variants of human ${\alpha}_1$-AT are unstable and cause pulmonary emphysema. However, the most clinically significant variant, Z-type ${\alpha}_1$-AT, exhibits retarded protein folding that leads to accumulation of folding intermediates. These aggregate within the endoplasmic reticulum (ER) of hepatocytes, subsequently causing liver cirrhosis as well as emphysema. Here, we studied the role of an ER folding assistant protein Cpr5p on Z-type ${\alpha}_1$-AT folding. Cpr5p was induced > 2-fold in Z-type ${\alpha}_1$-AT-expressing yeast cells compared with the wild type. Knockout of CPR5 exacerbated cytotoxicity of Z-type ${\alpha}_1$-AT, and re-introduction of CPR5 rescued the knockout cells from aggravated cytotoxicity caused by the ${\alpha}_1$-AT variant. Furthermore, Cpr5p co-immunoprecipitated with Z-type ${\alpha}_1$-AT and facilitated its protein folding. Our results suggest that protein-folding diseases may be suppressed by folding assistant proteins at the site of causal protein biosynthesis.

• BMB Reports
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• v.33 no.5
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• pp.379-384
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• 2000

The native conformation of serpins (serine protease inhibitors) is strained. Upon cleavage of the reactive center loop of serpins by a protease, the amino terminal portion of the cleaved loop is inserted into the central ${\beta}-sheet$, A sheet, as the fourth strand, with the concomitant release of the native strain. We questioned the role of protease in this conformational switch from the strained native form into a stable relaxed state. Chemical cleavage of the reactive center loop of ${\alpha}_1-antitrypsin$, a prototype serpin, using hydroxylamine dramatically increased the stability of the serpin. A circular dichroism spectrum and peptide binding study suggests that the amino terminal portion of the reactive center loop is inserted into the A sheet in the chemically-cleaved ${\alpha}_1-antitrypsin$, as in the enzymatically-cleaved molecule. These results indicate that the structural transformation of a serpin molecule does not require interaction with a protease. The results suggest that the serpin conformational switch that occurred during the complex formation with a target protease is induced by the cleavage of the reactive center loop per se.