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TitleHighly ordered clustering of TNFα and BAFF ligand-receptor-intracellular adaptor complexes on a lipid membrane.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 5551, Year 2025
Publish dateJul 1, 2025
AuthorsChan Seok Lim / Jisun Lee / Ji Won Kim / Jie-Oh Lee /
PubMed AbstractThe TNF family plays a critical role in immune regulation. Here, we present high-resolution structures of clusters formed by two TNF receptor family proteins, TNFR1 and BAFFR. Using a lipid monolayer ...The TNF family plays a critical role in immune regulation. Here, we present high-resolution structures of clusters formed by two TNF receptor family proteins, TNFR1 and BAFFR. Using a lipid monolayer method to mimic their membrane-bound state, we observe that the TNFα-TNFR1 complex forms highly ordered clusters of trimers on the lipid membrane. A non-competitive TNFR1 antagonist that inhibits receptor activation disrupted these clusters without blocking ligand binding or receptor trimerization. Furthermore, we find that the BAFF-BAFFR, BAFF-TACI, and BAFF-BCMA receptor-ligand complexes predominantly form pentagonal clusters of trimers on the lipid membrane. Notably, the binding of the intracellular adaptor TRAF3 to the BAFF-BAFFR complex induces a structural transition from a pentagonal to a flat hexagonal cluster. Mutations in BAFF that impair BAFFR activation prevented cluster formation. Our findings demonstrate that ligand binding induces the formation of highly ordered clusters of TNFR1 and BAFFR receptors on the lipid membrane, which is essential for their activation.
External linksNat Commun / PubMed:40593711 / PubMed Central
MethodsEM (single particle)
Resolution2.56 - 6.14 Å
Structure data

60484

8zui

EMDB-60484, PDB-8zui:
Binary cluster of TNF-TNFR1 ectodomain complex
Method: EM (single particle) / Resolution: 2.56 Å

60485

8zuj

EMDB-60485, PDB-8zuj:
Pentagonal cluster of BAFF-BAFFR ectodomain complex
Method: EM (single particle) / Resolution: 2.58 Å

60486

8zuk

EMDB-60486, PDB-8zuk:
Cluster structure of the BAFF-BAFFR-TRAF3 complex
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-60487: Pentagonal cluster of BAFF-BAFFR 3:3 complex
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-60488: Cluster structure of BAFF-BAFFR-TRAF3(His) complex
Method: EM (single particle) / Resolution: 3.77 Å

EMDB-60489: Linear bent cluster of TNF-TNFR1 ectodomain complex
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-60490: Binary cluster of TNF-TNFR1 full-length complex
Method: EM (single particle) / Resolution: 6.02 Å

EMDB-60491: Linear quadruple cluster of TNF-TNFR1 ectodomain complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-60492: Double pentagonal cluster of BAFF-BAFFR ectodomain complex
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-60493: Half spherical cluster of BAFF-BAFFR ectodomain complex
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-60494: Binary cluster of the TNF-TNFR1ecto-nanobody complex
Method: EM (single particle) / Resolution: 6.14 Å

EMDB-60497: Trigonal pyramid cluster of TNF-TNFR1 ectodomain complex
Method: EM (single particle) / Resolution: 5.17 Å

EMDB-63177: Pentagonal cluster of BAFF-TACI ectodomain complex
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-63178: Pentagonal cluster of BAFF-BCMA ectodomain complex
Method: EM (single particle) / Resolution: 2.56 Å

EMDB-63627: Quintuple cluster of TNF-TNFR1 ectodomain complex
Method: EM (single particle) / Resolution: 4.33 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / TNF receptor / Receptor / Receptor cluster / BAFF receptor / Signal complex / membrane receptor

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