Fu Qingshan, Fu Tian-Min, Cruz Anthony C, Sengupta Prabuddha, Thomas Stacy K, Wang Shuqing, Siegel Richard M, Wu Hao, Chou James J
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Mol Cell. 2016 Feb 18;61(4):602-613. doi: 10.1016/j.molcel.2016.01.009. Epub 2016 Feb 4.
Fas (CD95, Apo-1, or TNFRSF6) is a prototypical apoptosis-inducing death receptor in the tumor necrosis factor receptor (TNFR) superfamily. While the extracellular domains of TNFRs form trimeric complexes with their ligands and the intracellular domains engage in higher-order oligomerization, the role of the transmembrane (TM) domains is unknown. We determined the NMR structures of mouse and human Fas TM domains in bicelles that mimic lipid bilayers. Surprisingly, these domains use proline motifs to create optimal packing in homotrimer assembly distinct from classical trimeric coiled-coils in solution. Cancer-associated and structure-based mutations in Fas TM disrupt trimerization in vitro and reduce apoptosis induction in vivo, indicating the essential role of intramembrane trimerization in receptor activity. Our data suggest that the structures represent the signaling-active conformation of Fas TM, which appears to be different from the pre-ligand conformation. Analysis of other TNFR sequences suggests proline-containing sequences as common motifs for receptor TM trimerization.
Fas（CD95、Apo-1或TNFRSF6）是肿瘤坏死因子受体（TNFR）超家族中典型的诱导凋亡的死亡受体。虽然TNFR的细胞外结构域与其配体形成三聚体复合物，且细胞内结构域参与更高阶的寡聚化，但跨膜（TM）结构域的作用尚不清楚。我们确定了在模拟脂质双层的双分子层中，小鼠和人类Fas TM结构域的核磁共振结构。令人惊讶的是，这些结构域利用脯氨酸基序在同三聚体组装中形成最佳堆积，这与溶液中经典的三聚体卷曲螺旋不同。Fas TM中与癌症相关的基于结构的突变在体外破坏三聚化，并在体内降低凋亡诱导，表明膜内三聚化在受体活性中起关键作用。我们的数据表明，这些结构代表Fas TM的信号传导活性构象，这似乎与配体前构象不同。对其他TNFR序列的分析表明，含脯氨酸的序列是受体TM三聚化的常见基序。
