Thrombosis as a conformational disease

Abstract

Conformational diseases are a newly recognized group of heterogeneous disorders resulting from the conformational instability of individual proteins. Such instability allows the formation of intermolecular linkages between b-sheets, to give protein aggregation and inclusion body formation. The serpin family of serine protease inhibitors provides the best-studied examples of the structural changes involved. Notably, mutations of a-1-antitrypsin result in its intracellular polymerization and accumulation in the liver leading eventually to cirrhosis. Here we consider how other conformational changes in another serpin, antithrombin, can cause its inactivation with consequent thrombosis. Thirteen different missense mutations in antithrombin are associated with either oligomer formation or with conversion of the active molecule into an inactive latent form. Each of these variant antithrombins is associated with an increased risk of thrombosis that typically occurs in an unexpectedly severe and sudden form. The trigger for this episodic thrombosis is believed to be the sudden conformational transition of the antithrombin with an accompanying loss of inhibitory activity. But what causes the transition? This is still unclear, though a likely contributor is the increased body temperature that occurs with infections hence the frequency of episodes associated with the urinary infections of pregnancy. The search for other causes is important, as the conformational perturbation of normal antithrombin is likely to be a contributory cause to the sporadic and apparently idiopathic occurrence of venous thrombosis.