期刊
ANNUAL REVIEW OF BIOCHEMISTRY
卷 78, 期 -, 页码 147-176出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev.biochem.78.082107.133320
关键词
alpha(1)-antitrypsin; conformational disease; neuroserpin; serpinopathy polymerization
资金
- Medical Reseach Council (United Kingdom)
- Wellcome Trust
- Alpha-1 Foundation (United States)
- Papworth Hospital NHS Trust
- Wellcome Trust Intermediate Clinical Fellow.
- Medical Research Council [G0500306] Funding Source: researchfish
- MRC [G0500306] Funding Source: UKRI
Point mutations cause members of the serine protease inhibitor (serpin) superfamily to undergo a novel conformational transition, forming ordered polymers. These polymers characterize a group of diseases termed the serpinopathies. The formation of polymers underlies the retention of alpha(1)-antitrypsin within hepatocytes and of neuroserpin within neurons to cause cirrhosis and dementia, respectively. Point mutations of antithrombin, C1 inhibitor, alpha(1)-antichymotrypsin, and heparin cofactor II cause a similar conformational transition, resulting in a plasma deficiency that is associated with thrombosis, angioedema, and emphysema. Polymers of serpins can also form in extracellular tissues where they activate inflammatory cascades. This is best described for the Z variant of alpha(1)-antitrypsin in which the proinflammatory properties of polymers provide an explanation for both progressive emphysema and the selective advantage of this mutant allele. Therapeutic strategies are now being developed to block the aberrant conformational transitions and so treat the serpinopathies.
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