Hahne M, Peitsch M C, Irmler M, Schröter M, Lowin B, Rousseau M, Bron C, Renno T, French L, Tschopp J
Institute of Biochemistry, University of Lausanne, Switzerland.
Int Immunol. 1995 Sep;7(9):1381-6. doi: 10.1093/intimm/7.9.1381.
Mice homozygous for either the gld or lpr mutation develop autoimmune diseases and progressive lymphadenopathy. The lpr mutation is characterized by the absence of functional Fas, whereas gld mice exhibit an inactive FasL due to a point mutation proximal to the extracellular C-terminus. The structural repercussions of this amino acid substitution remain unknown. Here we report that FasL is expressed at similar levels on the surface of activated T lymphocytes from gld and wild-type mice. Using a polyclonal anti-FasL antibody, indistinguishable amounts of a 40 kDa protein are detected in both gld and wild-type splenocytes. The molecular model of FasL, based on the known structure of TNF-alpha, predicts that the Phe --> Leu gld mutation is located at the protomer interface which is close to the FasR interaction site. We conclude that the gld mutation allows normal FasL biosynthesis, surface expression and oligomerization, but induces structural alterations to the Fas binding region leading to the phenotypic changes observed.
纯合子携带gld或lpr突变的小鼠会患上自身免疫性疾病并出现进行性淋巴结病。lpr突变的特征是缺乏功能性Fas，而gld小鼠由于细胞外C末端附近的点突变而表现出无活性的FasL。这种氨基酸取代的结构影响尚不清楚。在此我们报告，FasL在gld小鼠和野生型小鼠活化T淋巴细胞表面的表达水平相似。使用多克隆抗FasL抗体，在gld和野生型脾细胞中检测到的40 kDa蛋白量无法区分。基于TNF-α已知结构的FasL分子模型预测，Phe→Leu的gld突变位于原聚体界面，该界面靠近FasR相互作用位点。我们得出结论，gld突变允许正常的FasL生物合成、表面表达和寡聚化，但会导致Fas结合区域的结构改变，从而导致观察到的表型变化。
