Structural and functional characterization of the abnormal Z α<sub>1</sub>‐antitrypsin isolated from human liver

Bathurst, Ian C.; Travis, James; George, Peter M.; Carrell, Robin W.

doi:10.1016/0014-5793(84)81279-x

Cited by 73 publications

(38 citation statements)

References 18 publications

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“…Although they are the most challenging to treat, some successes have been reported. Examples include the rescue of misfolded cystic fibrosis transmembrane regulator (CFTR) variant F508⌬ (44) and the Zvariant of ␣ 1 -antitrypsin (45). In the instance of CFTR, the osmolytes glycerol and trimethylamino-oxide have been used (46 -48).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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“…In previous studies a secretory abnormality in PiZZ a1PI deficiency has been inferred from analyses that allowed only static observations-i.e., immunocytochemistry, x-ray crystallography, and structural analysis of material isolated from liver inclusions (1)(2)(3)(4)12). Technical limitations in biosynthetic labeling and analytical methods in several recent studies examining biosynthesis and secretion of a1PI (25,29) have prevented definitive identification of the mechanism accounting for low serum concentrations in deficient individuals.…”

Section: Discussionmentioning

confidence: 99%

“…These inclusion bodies contain a1PI according to immunofluorescence studies and amino acid analysis of material isolated from the inclusions (1,2). Second, PiZZ a1PI isolated from intrahepatocyte inclusion bodies appears to be incompletely glycosylated (3,4). There is less sialic acid, galactose, and N-acetylglucosamine and more mannose in hepatic PiZZ a1PI, suggesting that core carbohydrates cannot undergo secondary processing.…”

mentioning

confidence: 99%

“…This conclusion was based on the crystal structure of a1PI complexed with serine protease, so that the conformation of intact native, plasma, or hepatic PiZZ a1PI can only be inferred. Furthermore, Bathurst et al (4) have shown that a1PI isolated from the liver of a PiZZ individual is functionally active, suggesting that it is in native conformation in the endoplasmic reticulum-Golgi axis.…”

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confidence: 99%

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The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA.

Perlmutter¹,

Kay²,

Cole³

et al. 1985

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

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“…␣1-Antitrypsin (or alpha 1-protease inhibitor, A1Pi) is a protease inhibitor that suppresses neutrophil-derived proteases in the serum and elastase activity in lung tissue. The classical form of A1Pi deficiency results from the Z variant (A1PiZ) that contains a K342E substitution (Bathurst et al, 1984;Crystal, 1990). A1PiZ homozygous individuals can develop emphysema via a loss-of-function mechanism because the altered conformation of A1PiZ results in its recognition and degradation by ERAD (Wu et al, 1994;Werner et al, 1996;Teckman et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Characterization of anERADGene asVPS30/ATG6Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human α-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

Kruse

Brodsky

McCracken

2006

MBoC

188

185

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The Z variant of human ␣-1 proteinase inhibitor (A1PiZ) is a substrate for endoplasmic reticulum-associated protein degradation (ERAD). To identify genes required for the degradation of this protein, A1PiZ degradation-deficient (add) yeast mutants were isolated. The defect in one of these mutants, add3, was complemented by VPS30/ATG6, a gene that encodes a component of two phosphatidylinositol 3-kinase (PtdIns 3-kinase) complexes: complex I is required for autophagy, whereas complex II is required for the carboxypeptidase Y (CPY)-to-vacuole pathway. We found that upon overexpression of A1PiZ, both PtdIns 3-kinase complexes were required for delivery of the excess A1PiZ to the vacuole. When the CPY-to-vacuole pathway was compromised, A1PiZ was secreted; however, disruption of autophagy led to an increase in aggregated A1PiZ rather than secretion. These results suggest that excess soluble A1PiZ transits the secretion pathway to the trans-Golgi network and is selectively targeted to the vacuole via the CPY-to-vacuole sorting pathway, but excess A1PiZ that forms aggregates in the endoplasmic reticulum is targeted to the vacuole via autophagy. These findings illustrate the complex nature of protein quality control in the secretion pathway and reveal multiple sites that recognize and sort both soluble and aggregated forms of aberrant or misfolded proteins. INTRODUCTIONCell function and survival depend on protein quality control to identify and remove aberrant proteins. Although two cellular sites of proteolysis are known, the lysosome/vacuole and cytoplasmic 26S proteasome, the recognition of aberrant proteins and mechanisms for delivery to these sites are still being defined. Endoplasmic reticulum-associated degradation (ERAD) is a protein quality control process in which aberrant or misassembled proteins in the secretory pathway are identified and removed (reviewed in Hampton, 2002;Tsai et al., 2002;Kostova and Wolf, 2003;McCracken and Brodsky, 2003). After entering the endoplasmic reticulum (ER), a nascent protein that fails to fold or assemble properly can be "recognized" by the ER quality control machinery, retained within the ER, and then retrotranslocated to the cytoplasm where it is degraded by the proteasome.The recognition of ERAD substrates must exhibit flexibility to distinguish slowly folding proteins from aberrant proteins. Molecular chaperones play a critical role in this selection process; for example, the ER heat-shock protein (Hsp70), BiP, is vital for the selection of soluble substrates and is believed to hold the substrates in an unfolded state competent for retrotranslocation (Nishikawa et al., 2001;Kabani et al., 2003).The complexity of the ERAD pathway has emerged with the identification of new ERAD substrates and the components required for their selection and degradation in yeast. For example, the analysis of topologically distinct ERAD substrates indicates that molecular chaperones in the cytoplasm and in the ER lumen distinguish membrane and soluble substrates, respectively (Huyer et al., 20...

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Structural and functional characterization of the abnormal Z α₁‐antitrypsin isolated from human liver

Abstract: α1‐Antitrypsin Human liver Inclusion body High mannose glycoprotein Proteinase inhibitor

Cited by 73 publications

References 18 publications

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA.

Characterization of anERADGene asVPS30/ATG6Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human α-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

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Structural and functional characterization of the abnormal Z α1‐antitrypsin isolated from human liver

Abstract: α1‐Antitrypsin Human liver Inclusion body High mannose glycoprotein Proteinase inhibitor

Cited by 73 publications

References 18 publications

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA.

Characterization of anERADGene asVPS30/ATG6Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human α-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

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Structural and functional characterization of the abnormal Z α₁‐antitrypsin isolated from human liver