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Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis.
Mahadeva R
,
Chang WS
,
Dafforn TR
,
Oakley DJ
,
Foreman RC
,
Calvin J
,
Wight DG
,
Lomas DA
.
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The association between Z alpha1-antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z alpha1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S alpha1-antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z alpha1-antitrypsin and another conformationally unstable variant (I alpha1-antitrypsin; 39Arg-->Cys) identified in a 34-year-old man with cirrhosis related to alpha1-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z alpha1-antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.
Aulak,
A hinge region mutation in C1-inhibitor (Ala436-->Thr) results in nonsubstrate-like behavior and in polymerization of the molecule.
1993, Pubmed
Aulak,
A hinge region mutation in C1-inhibitor (Ala436-->Thr) results in nonsubstrate-like behavior and in polymerization of the molecule.
1993,
Pubmed
Baur,
Study of familial alpha-1-proteinase inhibitor deficiency including a rare proteinase inhibitor phenotype (IZ). I. Alpha-1-phenotyping and clinical investigations.
1987,
Pubmed
Brantly,
Molecular basis of alpha-1-antitrypsin deficiency.
1988,
Pubmed
Bruce,
Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp).
1994,
Pubmed
Campra,
Cirrhosis associated with partial deficiency of alpha-1 antitrypsin in an adult.
1973,
Pubmed
Carrell,
Structure and variation of human alpha 1-antitrypsin.
1982,
Pubmed
Carrell,
Biological implications of a 3 A structure of dimeric antithrombin.
1994,
Pubmed
Chang,
Probing serpin reactive-loop conformations by proteolytic cleavage.
1996,
Pubmed
Colp,
Variants of alpha 1-antitrypsin in Puerto Rican children with asthma.
1993,
Pubmed
Cruz,
Cirrhosis and heterozygous alpha1-antitrypsin deficiency in a 4-year-old girl.
1976,
Pubmed
Eldering,
COOH-terminal substitutions in the serpin C1 inhibitor that cause loop overinsertion and subsequent multimerization.
1995,
Pubmed
Elliott,
Inhibitory conformation of the reactive loop of alpha 1-antitrypsin.
1996,
Pubmed
Elliott,
Structural explanation for the deficiency of S alpha 1-antitrypsin.
1996,
Pubmed
Elliott,
Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation.
1998,
Pubmed
Eriksson,
Studies in alpha 1-antitrypsin deficiency.
1965,
Pubmed
Eriksson,
Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency.
1986,
Pubmed
Esnault,
Alpha 1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis.
1993,
Pubmed
Fagerhol,
Serum Pi types in some European, American, Asian and African populations.
1968,
Pubmed
Graham,
Molecular characterisation of three alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) nullcardiff (Asp256----Val); PiMmalton (Phe51----deletion) and PiI (Arg39----Cys).
1989,
Pubmed
Hodges,
Heterozygous MZ alpha 1-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis.
1981,
Pubmed
Huber,
Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins.
1989,
Pubmed
Johnson,
Structural evidence for methionine at the reactive site of human alpha-1-proteinase inhibitor.
1978,
Pubmed
King,
Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT.
1996,
Pubmed
Koloczek,
Serpin alpha 1proteinase inhibitor probed by intrinsic tryptophan fluorescence spectroscopy.
1996,
Pubmed
Le,
Soluble aggregates of the human PiZ alpha 1-antitrypsin variant are degraded within the endoplasmic reticulum by a mechanism sensitive to inhibitors of protein synthesis.
1992,
Pubmed
Lindo,
Antithrombin-TRI (Ala382 to Thr) causing severe thromboembolic tendency undergoes the S-to-R transition and is associated with a plasma-inactive high-molecular-weight complex of aggregated antithrombin.
1995,
Pubmed
Lomas,
The mechanism of Z alpha 1-antitrypsin accumulation in the liver.
1992,
Pubmed
Lomas,
Effect of the Z mutation on the physical and inhibitory properties of alpha 1-antitrypsin.
1993,
Pubmed
Lomas,
Alpha 1-antitrypsin Siiyama (Ser53-->Phe). Further evidence for intracellular loop-sheet polymerization.
1993,
Pubmed
Lomas,
Preparation and characterization of latent alpha 1-antitrypsin.
1995,
Pubmed
Lomas,
alpha 1-Antitrypsin Mmalton (Phe52-deleted) forms loop-sheet polymers in vivo. Evidence for the C sheet mechanism of polymerization.
1995,
Pubmed
,
Xenbase
Morin,
Heterozygous alpha 1-antitrypsin deficiency and cirrhosis in adults, a fortuitous association.
1975,
Pubmed
Pemberton,
Hormone binding globulins undergo serpin conformational change in inflammation.
1988,
Pubmed
Potempa,
The serpin superfamily of proteinase inhibitors: structure, function, and regulation.
1994,
Pubmed
Roberts,
Occurrence of alpha-1-antitrypsin deficiency in 155 patients with alcoholic liver disease.
1984,
Pubmed
Segelmark,
The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis.
1995,
Pubmed
Selvin,
Fluorescence resonance energy transfer.
1995,
Pubmed
Seyama,
Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)). A new alpha 1-antitrypsin-deficient variant with mutation on a predicted conserved residue of the serpin backbone.
1991,
Pubmed
Sidhar,
Mutations which impede loop/sheet polymerization enhance the secretion of human alpha 1-antitrypsin deficiency variants.
1995,
Pubmed
,
Xenbase
Stein,
What do dysfunctional serpins tell us about molecular mobility and disease?
1995,
Pubmed
Sveger,
Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants.
1976,
Pubmed