2. Academic Validation
  3. Electric dipole moment drives the dynamics of the TNFR1 complex I signalosome

Electric dipole moment drives the dynamics of the TNFR1 complex I signalosome

  • Nature. 2026 May;653(8116):1196-1204. doi: 10.1038/s41586-026-10304-1.
Jianping Liu # 1,  Jing Zhao # 2 3,  Jiayang Gao # 2 3,  Kun Zhao 2 3,  Yaoyao Han 2 3,  Jing Yang 2 4,  Zefei Li 2 3,  Jianyu Ye 2 3,  Ziyu Sun 2 3,  Fengyi Wang 2 3,  Xinyi Liu 2 3,  Zekai Li 2 3,  Siyu Ji 2 3,  Bo Liu 2,  Cong Liu 2,  Yixiao Zhang 2,  Junying Yuan 5,  James J Chou 6 7
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai, China.
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 6 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 7 State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41922760 DOI: 10.1038/s41586-026-10304-1
Abstract

Dynamic assembly of the complex I signalosome mediated by three death domain (DD)-containing proteins-TNFR1, TRADD and RIPK1-is key for transmitting extracellular TNF stimuli to intracellular NF-κB signalling in controlling 'live or die' cell fate1. This signalling hub features the rapid recruitment of TRADD and RIPK1 after engagement of TNFR1 by TNF for the formation of complex I, followed by timed disassembly for transition into downstream signalling complexes2,3, but the mechanism driving the dynamic reversibility of complex I remains unclear. Here we captured the assembly core of complex I and determined its cryo-electron microscopy structure, showing a pentameric fibre comprising 31 DDs, with a single layer of a TRADD-DD pentamer sandwiched between multiple layers of TNFR1-DD and RIPK1-DD homopentamers. Structural analysis revealed a strong opposing electric dipole moment (EDM) generated by RIPK1-DD oligomerization relative to that of TNFR1-DD and TRADD-DD. Structure-guided mutagenesis in TNFR1-TRADD-RIPK1 pentameric fibres altering the EDM without affecting DD oligomerization demonstrated the role and mechanism of EDM in driving the dynamic reversibility mediating the rapid assembly and disassembly of complex I. Our study demonstrates a role for long-range interactions mediated by protein EDMs in driving the assembly and disassembly of super-signalling complex I for promoting NF-κB signalling.

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