Moritz W, Froesch E R, Böni-Schnetzler M
Department of Internal Medicine, University Hospital, Zurich, Switzerland.
FEBS Lett. 1994 Sep 5;351(2):276-80. doi: 10.1016/0014-5793(94)00876-0.
We analysed the biochemical properties of insulin receptors of a Type A insulin resistant patient with a single heterozygous point mutation substituting Gln for Arg1174. Insulin binding capacity and affinity to Epstein-Barr virus transformed lymphocytes was normal. Quantitative analysis of autophosphorylation and substrate phosphorylation of soluble insulin receptors isolated from patient cells revealed no differences in the basal state whereas in the presence of insulin autophosphorylation activity was only 30% of control receptors. The stimulation of substrate phosphorylation and down-regulation of receptors on patient cells after chronic exposure to insulin was diminished when compared to controls. We conclude that the heterozygous Arg1174 mutation does not perturb basal kinase activity but specifically interferes with the kinase activation by insulin and that the mutation has a dominant negative effect on the wild type kinase.
我们分析了一名A型胰岛素抵抗患者胰岛素受体的生化特性，该患者存在一个杂合点突变，用谷氨酰胺替代了精氨酸1174。胰岛素与爱泼斯坦-巴尔病毒转化淋巴细胞的结合能力和亲和力正常。对从患者细胞中分离出的可溶性胰岛素受体进行自磷酸化和底物磷酸化的定量分析显示，基础状态下无差异，而在胰岛素存在时，自磷酸化活性仅为对照受体的30%。与对照组相比，慢性暴露于胰岛素后患者细胞上底物磷酸化的刺激和受体下调减弱。我们得出结论，杂合的精氨酸1174突变不会干扰基础激酶活性，但会特异性地干扰胰岛素对激酶的激活，并且该突变对野生型激酶具有显性负效应。
