Cited by 191Cell death mechanisms and regulationProtein Structure and DynamicsReceptor Mechanisms and Signaling

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

Open access
Fu, Qingshan, Fu, Tian-Min, Cruz, Anthony C., Sengupta, Prabuddha, Thomas, Stacy K., Wang, Shuqing, Siegel, Richard M., Wu, Hao +1 more·2016·Molecular Cell

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.

Integrity signals

Registry

Crossref · 10.1016/j.molcel.2016.01.009

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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)”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2016-02
Volume
61
Issue
4
Pages
602-613
ISSN
1097-2765 (ISSN-L)
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review