title: Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor.
abstract: 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.
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors: Qingshan
authors: Q
authors: Fu
authors: 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.
authors: Tian-Min
authors: TM
authors: Fu
authors: Immunoregulation Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors: Anthony C
authors: AC
authors: Cruz
authors: Section on Organelle Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
authors: Prabuddha
authors: P
authors: Sengupta
authors: Immunoregulation Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors: Stacy K
authors: SK
authors: Thomas
authors: School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors: Shuqing
authors: S
authors: Wang
authors: Immunoregulation Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors: Richard M
authors: RM
authors: Siegel
authors: 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. Electronic address: wu@crystal.harvard.edu.
authors: Hao
authors: H
authors: Wu
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: chou@crystal.harvard.edu.
authors: James J
authors: JJ
authors: Chou
mesh_terms: D000818:Animals; D017209:Apoptosis; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D011392:Proline / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019014:fas Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; C491899:Fas protein, mouse; D008051:Lipid Bilayers; D019014:fas Receptor; D011392:Proline