Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor
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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.
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FAS and TRAILR ligands stabilize preformed receptor homotrimers to induce a conformational change enabling DD-dependent FADD association.
“In the case of FAS and TRAILRs, the cognate ligands—namely, FAS ligand (FASLG; also known as CD95L or APO-1L) and TNF superfamily member 10 (TNFSF10; best known as TRAIL), respectively—stabilize preformed receptor homotrimers to induce a conformational change at their intracellular tails that enables the death domain (DD)-dependent association of the adapter Fas associated via death domain (FADD)”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [282]
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- Authors
- Fu, Q., Fu, T.-M., Cruz, A. C., Sengupta, P., Thomas, S. K., Wang, S., Siegel, R. M., Wu, H., & Chou, J. J.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- National Institutes of Health (US)
- Tianjin Medical University (CN)
- Corresponding author
- Wu, Hao
- Chou, James J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 61
- Issue
- 4
- Pages
- 602-613
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4761300
- OpenAlex
- W2252441686
- Cited by
- 191
- References
- 43
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 21 · 2023: 14 · 2022: 26 · 2021: 24 · 2020: 15 · 2019: 25 · 2018: 12 · 2017: 9 · 2016: 14
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL103526, HL103526)
- National Institute of Allergy and Infectious Diseases (R37AI050872, AI050872, R01AI050872, R01AI045937)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01AR041133)
- National Institute of Biomedical Imaging and Bioengineering (P41EB002026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Fas/CD95, death receptors, transmembrane domain, proline-rich motif, apoptosis signaling, receptor oligomerization, cancer-associated mutations, ligand-induced conformational change
- MeSH terms
- Animals, HeLa Cells, Humans, Lipid Bilayers, Magnetic Resonance Imaging, Models, Molecular, Mutation, Proline, Signal Transduction, Apoptosis, Protein Structure, Tertiary, fas Receptor, Mice, Protein Multimerization, HEK293 Cells
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