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

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 ro...

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Bibliographic Details
Published in:Molecular cell 2016-02, Vol.61 (4), p.602-613
Main Authors: Fu, Qingshan, Fu, Tian-Min, Cruz, Anthony C., Sengupta, Prabuddha, Thomas, Stacy K., Wang, Shuqing, Siegel, Richard M., Wu, Hao, Chou, James J.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
fas Receptor - chemistry
fas Receptor - genetics
fas Receptor - metabolism
HEK293 Cells
HeLa Cells
Humans
Lipid Bilayers - metabolism
Magnetic Resonance Imaging
Mice
Models, Molecular
Mutation
Proline - metabolism
Protein Multimerization
Protein Structure, Tertiary
Signal Transduction
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Summary: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. [Display omitted] •Fas transmembrane domain structures show proline-containing motif for trimerization•The trimer conformation of the transmembrane domain is important for Fas signaling•The trimer conformation represents signaling-active, but not pre-liganded, state of Fas•Structural and functional data explain cancer mutations in transmembrane domain Fas/CD95 is an apoptosis-inducing death receptor. Fu et al. determined the transmembrane domain structure of Fas and showed that the trimer assembly, which is mediated by a proline-containing motif, is essential for Fas signaling. The study provides structural explanation for several known cancer mutations in the transmembrane domain of Fas.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2016.01.009