Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor

被引:139
作者
Fu, Qingshan [1 ]
Fu, Tian-Min [1 ,2 ]
Cruz, Anthony C. [3 ]
Sengupta, Prabuddha [4 ]
Thomas, Stacy K. [3 ]
Wang, Shuqing [5 ]
Siegel, Richard M. [3 ]
Wu, Hao [1 ,2 ]
Chou, James J. [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[2] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
[3] NIAMSD, Immunoregulat Sect, NIH, Bethesda, MD 20892 USA
[4] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Organelle Biol, NIH, Bethesda, MD 20892 USA
[5] Tianjin Med Univ, Sch Pharm, Tianjin 300070, Peoples R China
关键词
NECROSIS-FACTOR RECEPTOR; PLASMA-MEMBRANE; PROTON CHANNEL; FAS MUTATIONS; EGF RECEPTOR; DOMAIN; COMPLEX; REVEALS; ARCHITECTURE; ASSOCIATION;
D O I
10.1016/j.molcel.2016.01.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:602 / 613
页数:12
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