1932

Abstract

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 α-antitrypsin within hepatocytes and of neuroserpin within neurons to cause cirrhosis and dementia, respectively. Point mutations of antithrombin, C1 inhibitor, α-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 α-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.

Loading

Article metrics loading...

/content/journals/10.1146/annurev.biochem.78.082107.133320
2009-07-07
2024-04-17
Loading full text...

Full text loading...

/content/journals/10.1146/annurev.biochem.78.082107.133320
Loading
/content/journals/10.1146/annurev.biochem.78.082107.133320
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error