Plakalbumin, alpha 1-antitrypsin, antithrombin and the mechanism of inflammatory thrombosis.
An old puzzle in protein biochemistry concerns the ready conversion of ovalbumin, by proteolysis, to the much more stable derivative, plakalbumin. Ovalbumin is now known to belong to the serpin superfamily, most of which are serine proteinase inhibitors. We report here studies of two such members of the family, the human plasma proteins alpha 1-antitrypsin and antithrombin, and show that they undergo a similar change in stability on selective proteolysis. This change, which is accompanied by a loss of inhibitory activity, can best be considered as an irreversible molecular transition from a native stressed (S) conformation, to a more ordered relaxed (R) form. The maintenance of the native S conformation, and hence the maintenance of inhibitory activity, is critically dependent on the integrity of an exposed loop of polypeptide. We propose that the susceptibility of this peptide loop to proteolytic cleavage gives it an incidental role as a physiological switch which allows the inactivation of individual inhibitors by specific proteolysis. The vulnerability of this exposed loop in each inhibitor also explains the pathological action of a number of venoms and toxins. In particular, the demonstration here of the cleavage of antithrombin, by leukocyte elastase, explains an observed change in blood coagulation that accompanies severe inflammation and which can result in fatal thrombosis.
D000818:Animals; D000991:Antithrombins / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation / Q000150:complications; D008657:Metabolic Clearance Rate; D009504:Neutrophils / Q000201:enzymology; D010047:Ovalbumin / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013927:Thrombosis / Q000209:etiology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D000991:Antithrombins; D010446:Peptide Fragments; D000515:alpha 1-Antitrypsin; C038141:plakalbumin; D010047:Ovalbumin; D010196:Pancreatic Elastase