Conformational pathology of the serpins: Themes, variations, and therapeutic strategies

Bibekbrata Gooptu, D.A. Lomas

    Research output: Contribution to journalArticlepeer-review

    224 Citations (Scopus)

    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 α1-antitrypsin within hepatocytes and of neuroserpin within neurons to cause cirrhosis and dementia, respectively. Point mutations of antithrombin, C1 inhibitor, α1-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 α1-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.
    Original languageEnglish
    Pages (from-to)147-176
    Number of pages30
    JournalAnnual Review of Biochemistry
    Volume78
    DOIs
    Publication statusPublished - 1 Jan 2009

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