Carrell R W, Owen M C
Nature. 1985;317(6039):730-2. doi: 10.1038/317730a0.
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.
蛋白质生物化学中的一个老难题涉及卵清蛋白通过蛋白水解迅速转化为稳定性更高的衍生物 plakalbumin。现在已知卵清蛋白属于丝氨酸蛋白酶抑制剂超家族，其中大多数是丝氨酸蛋白酶抑制剂。我们在此报告对该家族的两个成员，即人血浆蛋白α1 -抗胰蛋白酶和抗凝血酶的研究，并表明它们在选择性蛋白水解时稳定性发生了类似变化。这种变化伴随着抑制活性的丧失，最恰当的理解是从天然应激（S）构象到更有序的松弛（R）形式的不可逆分子转变。天然S构象的维持，进而抑制活性的维持，关键取决于一条暴露的多肽环的完整性。我们提出，这条肽环对蛋白水解切割的敏感性使其具有作为生理开关偶尔发挥的作用，该开关允许通过特定蛋白水解使单个抑制剂失活。每种抑制剂中这条暴露环的脆弱性也解释了许多毒液和毒素的病理作用。特别是，这里展示的白细胞弹性蛋白酶对抗凝血酶的切割，解释了严重炎症伴随的血液凝固变化，这种变化可能导致致命血栓形成。
