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

## Summary
Article ADS CAS PubMed PubMed Central Google Scholar Jiang, Y., Woronicz, J. Article ADS CAS PubMed PubMed Central Google Scholar Wertz, I. Article ADS CAS PubMed PubMed Central Google Scholar Park, H. Article ADS CAS PubMed PubMed Central Google Scholar Steeland, S. et al.

## Article Content
Subjects
Cryoelectron microscopy
NF-kappaB
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 fate
1
. 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 complexes
2
,
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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Fig. 1: TNFR1-DD, TRADD-DD and RIPK1-DD assemble into a superternary complex.
Fig. 2: The structural basis for TRADD-DD pentamer as the adaptor for complex I formation.
Fig. 3: Homotypic oligomerization of TNFR1-DD and RIPK1-DD is critical for complex I signalling.
Fig. 4: Homotypic stoichiometry of TNFR1-DD in receptor clustering and complex I formation.
Fig. 5: Regulation of complex I dynamics by protein EDM.
Data availability
The atomic coordinates and cryo-EM density maps reported in this study have been deposited in the Protein Data Bank and Electron Microscopy Data Bank under accession codes
9V9C
and
EMD-64869
(TNFR1-DD filament),
9VGD
and
EMD-65047
(TRADD-DD filament),
9V9E
and
EMD-64870
(RIPK1-DD filament) and
9VIN
and
EMD-65094
(TNFR1-DD–TRADD-DD–RIPK1-DD ternary complex).
Source data
are provided with this paper.
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## Expert Analysis

### Merits
- Structural analysis revealed a strong opposing electric dipole moment (EDM) generated by RIPK1-DD oligomerization relative to that of TNFR1-DD and TRADD-DD.

### Areas for Consideration
- 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 complexes 2 , 3 , but the mechanism driving the dynamic reversibility of complex I remains unclear.

### Implications
- Go to natureasia.com Buy this article Purchase on SpringerLink Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Fig. 1: TNFR1-DD, TRADD-DD and RIPK1-DD assemble into a superternary complex.
- Fig. 5: Regulation of complex I dynamics by protein EDM.
- Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death.
- Ubiquitin-mediated regulation of TNFR1 signaling.

### Expert Commentary
This article covers pubmed, article, google topics. Notable strengths include discussion of pubmed. Areas of concern are also raised. Readability: Flesch-Kincaid grade 0.0. Word count: 2293.