Variability in purified dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies.
Variability in purified dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies.
复制标题
遗传性血管神经性水肿患者纯化的功能失调 C1(-) 抑制剂蛋白的变异性。
DOI：
10.1172/jci111664
复制
发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Awad,S
中科院分区：
文献类型：
--
作者：
Donaldson,VH;Harrison,RA;Rosen,FS;Bing,DH;Kindness,G;Canar,J;Wagner,CJ;Awad,S
我们比较了正常人和与遗传性血管神经性水肿（HANE）相关的8种不同的C1(-)-inh蛋白功能失调的亲属的C1(-)-inh蛋白对纯化的C1s-制剂、血浆钾激肽肽、活化形式的Hageman因子和血浆溶酶的抑制活性。每种功能失调的C1(-)- inh蛋白对这些酶表现出独特的抑制活性谱。尽管功能失调的C1(-)- inh蛋白均未显著损害纤溶酶的酶解，但除一种外，其余均抑制活化的Hageman因子。一个纯化的功能失调的C1(-)- inh （Ta）抑制纯化的C1s-到正常程度。另一种C1(-)- inh （Za）对活化Hageman因子的抑制活性几乎是正常C1(-)- inh的7倍，但对C1s-的抑制活性降低，对纤溶酶无活性。对纤溶蛋白和C1(-)- inh蛋白混合物的SDS凝胶电泳分析显示，暴露于C1s-和纤溶蛋白后，功能失调蛋白的复合物形成和切割模式发生了变化。一些与纤溶酶结合并被切割，即使没有明显损害纤溶酶的酶解活性。其中两个被C1s-切割，而正常或其他功能失调的C1(-)- inh都没有被切割。因此，HANE患者体内功能失调的C1(-)- inh蛋白的抑制特性是异质的，对正常C1(-)- inh所能调节的各种血浆酶的抑制一定有不同的结构要求。数据表明，除了这些蛋白酶和C1(-)- inh之间的共同相互作用位点外，还存在针对每种蛋白酶的特异性接触点。基因突变导致其中一些位点的结构改变，可能对单个蛋白酶和异常C1(-)- inh蛋白之间的相互作用产生不同的影响。这些改变可能允许这些蛋白作为正常C1(-)- inh抑制作用的结构要求的探针。图片
C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin. Each dysfunctional C1(-)-INH protein showed a unique spectrum of inhibitory activity against these enzymes. Although none of the dysfunctional C1(-)-INH proteins significantly impaired amidolysis by plasmin, all but one inhibited activated Hageman factor. One purified dysfunctional C1(-)-INH (Ta) inhibited purified C1s- to a normal degree. Another C1(-)-INH (Za) had almost seven times as much inhibitory activity as normal C1(-)-INH against activated Hageman factor, but had decreased activity against C1s- and no activity against plasmin. Analyses of mixtures of plasmin and C1(-)-INH proteins in SDS gel electrophoresis revealed variability in the patterns of complex formation and cleavage of dysfunctional proteins after exposure to C1s- and plasmin. Some bound to plasmin and were cleaved, even though none significantly impaired the amidolytic activity of plasmin. Two were cleaved by C1s-, whereas neither normal or other dysfunctional C1(-)-INH were cleaved. Dysfunctional C1(-)-INH proteins from patients with HANE are thus heterogeneous in their inhibitory properties and there must be different structural requirements for the inhibition of the various plasma enzymes that can be regulated by normal C1(-)-INH. The data suggest that in addition to common sites of interactions between these proteases and C1(-)-INH, there are also points of contact that are specific for each protease. Genetic mutations leading to structural changes at some of these sites may have differing effects on the interaction between individual proteases and abnormal C1(-)-INH proteins. These alterations may allow these proteins to serve as probes for structural requirements for inhibitory actions of normal C1(-)-INH.Images