Journal Article

Highly ordered clustering of TNFα and BAFF ligand-receptor-intracellular adaptor complexes on a lipid membrane

Lee, Jisun, Kim, Ji Won, Lim, Chan Seok, Lee, Jie-Oh

2025

Overview

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. The TNF family regulates immune responses. Here, the authors used cryo-EM and a lipid membrane system to reveal how TNFR1 and BAFFR receptors form clusters, demonstrating that this higher-order assembly is essential for proper receptor signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 101/28 / 631/250/516/1909 / 631/45/269 / 631/535/1258/1259 / 631/57/2271 / 82/80 / 82/83 / Adapters / Adaptor proteins / Apoptosis / B-Cell Activating Factor - chemistry / B-Cell Activating Factor - genetics / B-Cell Activating Factor - metabolism / B-Cell Activation Factor Receptor - chemistry / B-Cell Activation Factor Receptor - genetics / B-Cell Activation Factor Receptor - metabolism / Binding / BLyS protein / Cell Membrane - metabolism / Clustering / Humanities and Social Sciences / Humans / Immune response / Immunoregulation / Intracellular / Ligands / Lipids / Membrane Lipids - chemistry / Membrane Lipids - metabolism / Membranes / Microscopy / multidisciplinary / Protein Binding / Protein Multimerization / Proteins / Receptor mechanisms / Receptors / Receptors, Tumor Necrosis Factor, Type I - chemistry / Receptors, Tumor Necrosis Factor, Type I - genetics / Receptors, Tumor Necrosis Factor, Type I - metabolism / Science / Science (multidisciplinary) / Signal transduction / TNF Receptor-Associated Factor 3 - chemistry / TNF Receptor-Associated Factor 3 - metabolism / Transcription factors / Transmembrane Activator and CAML Interactor Protein - chemistry / Transmembrane Activator and CAML Interactor Protein - metabolism / Trimers / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha - chemistry / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / Tumor necrosis factor-α