Document Detail

New insights into the structural basis of alpha 1-antitrypsin deficiency.
MedLine Citation:
PMID:  8977959     Owner:  NLM     Status:  MEDLINE    
The serpin superfamily of serine proteinase inhibitors contains many members but the best-characterized is the plasma protein alpha 1-antitrypsin. its genetic deficiency is associated, in the homozygote, with hepatic damage that may progress to cirrhosis and hepatocellular carcinoma. Low levels of circulating alpha 1-antitrypsin fail to protect the lungs against proteolytic attack and predispose the homozygote to early onset pan-lobular emphysema, bronchiectasis and asthma. The major cause of alpha 1-antitrypsin deficiency, the Z mutation (Glu342Lys), results in the accumulation of protein in the endoplasmic reticulum of the liver. Using a structural approach, we have shown that the hepatic inclusions result from a protein-protein interaction between the reactive centre loop of one molecule and the beta-pleated sheet of a second. This loop-sheet polymerization is now also recognized to be the basis of deficiencies associated with mutations of C1-inhibitor, antithrombin and alpha 1-antichymotrypsin. Our recent solution of a crystal structure of a thermostable mutant of alpha 1-antitrypsin shows the detailed interactions that result in loop-sheet linkage and helps to explain the mechanism of action of this family of proteinase inhibitors.
D A Lomas
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  QJM : monthly journal of the Association of Physicians     Volume:  89     ISSN:  1460-2725     ISO Abbreviation:  QJM     Publication Date:  1996 Nov 
Date Detail:
Created Date:  1997-01-10     Completed Date:  1997-01-10     Revised Date:  2005-11-16    
Medline Journal Info:
Nlm Unique ID:  9438285     Medline TA:  QJM     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  807-12     Citation Subset:  IM    
Department of Medicine, University of Cambridge, MRC Centre, UK.
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MeSH Terms
Linkage (Genetics)
Liver Diseases / etiology
Models, Molecular
Molecular Structure
Point Mutation
Protein Conformation
Serpins / chemistry
alpha 1-Antitrypsin / chemistry
alpha 1-Antitrypsin Deficiency*
Reg. No./Substance:
0/Serpins; 0/alpha 1-Antitrypsin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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