skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex

Abstract

The RIPK1-RIPK3 necrosome is an amyloid signaling complex that initiates TNF-induced necroptosis, serving in human immune defense, cancer, and neurodegenerative diseases. RIPK1 and RIPK3 associate through their RIP homotypic interaction motifs with consensus sequences IQIG (RIPK1) and VQVG (RIPK3). Using solid-state nuclear magnetic resonance, we determined the high-resolution structure of the RIPK1-RIPK3 core. RIPK1 and RIPK3 alternately stack (RIPK1, RIPK3, RIPK1, RIPK3, etc.) to form heterotypic β sheets. Two such β sheets bind together along a compact hydrophobic interface featuring an unusual ladder of alternating Ser (from RIPK1) and Cys (from RIPK3). The crystal structure of a four-residue RIPK3 consensus sequence is consistent with the architecture determined by NMR. In conclusion, the RIPK1-RIPK3 core is the first detailed structure of a hetero-amyloid and provides a potential explanation for the specificity of hetero- over homo-amyloid formation and a structural basis for understanding the mechanisms of signal transduction.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [6];  [7]
  1. Columbia Univ., New York, NY (United States); Univ. of Castile-La Mancha, Ciudad Real (Spain)
  2. Columbia Univ., New York, NY (United States); Johns Hopkins Univ., Baltimore, MD (United States)
  3. Fudan Univ., Shanghai (China); Boston Children's Hospital, Boston, MA (United States)
  4. Columbia Univ., New York, NY (United States); Adocia, Lyon (France)
  5. Columbia Univ., New York, NY (United States); Keck School of Medicine of USC, Los Angeles, CA (United States)
  6. Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  7. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF); National Key Research and Development Program of China; National Natural Science Foundation of China (NNSFC)
OSTI Identifier:
1438888
Grant/Contract Number:  
R01 AI045937; MCB 0749381; MCB 1412253; 2016YFA0500600; 31670878
Resource Type:
Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 173; Journal Issue: 5; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; SSNMR; solid state NMR; NMR structure; hetero-amyloid; functional amyloid; RHIM; RIPK1; RIPK3; signaling complex; X-ray crystallography

Citation Formats

Mompeán, Miguel, Li, Wenbo, Li, Jixi, Laage, Ségolène, Siemer, Ansgar B., Bozkurt, Gunes, Wu, Hao, and McDermott, Ann E. The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex. United States: N. p., 2018. Web. doi:10.1016/j.cell.2018.03.032.
Mompeán, Miguel, Li, Wenbo, Li, Jixi, Laage, Ségolène, Siemer, Ansgar B., Bozkurt, Gunes, Wu, Hao, & McDermott, Ann E. The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex. United States. doi:https://doi.org/10.1016/j.cell.2018.03.032
Mompeán, Miguel, Li, Wenbo, Li, Jixi, Laage, Ségolène, Siemer, Ansgar B., Bozkurt, Gunes, Wu, Hao, and McDermott, Ann E. Thu . "The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex". United States. doi:https://doi.org/10.1016/j.cell.2018.03.032. https://www.osti.gov/servlets/purl/1438888.
@article{osti_1438888,
title = {The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex},
author = {Mompeán, Miguel and Li, Wenbo and Li, Jixi and Laage, Ségolène and Siemer, Ansgar B. and Bozkurt, Gunes and Wu, Hao and McDermott, Ann E.},
abstractNote = {The RIPK1-RIPK3 necrosome is an amyloid signaling complex that initiates TNF-induced necroptosis, serving in human immune defense, cancer, and neurodegenerative diseases. RIPK1 and RIPK3 associate through their RIP homotypic interaction motifs with consensus sequences IQIG (RIPK1) and VQVG (RIPK3). Using solid-state nuclear magnetic resonance, we determined the high-resolution structure of the RIPK1-RIPK3 core. RIPK1 and RIPK3 alternately stack (RIPK1, RIPK3, RIPK1, RIPK3, etc.) to form heterotypic β sheets. Two such β sheets bind together along a compact hydrophobic interface featuring an unusual ladder of alternating Ser (from RIPK1) and Cys (from RIPK3). The crystal structure of a four-residue RIPK3 consensus sequence is consistent with the architecture determined by NMR. In conclusion, the RIPK1-RIPK3 core is the first detailed structure of a hetero-amyloid and provides a potential explanation for the specificity of hetero- over homo-amyloid formation and a structural basis for understanding the mechanisms of signal transduction.},
doi = {10.1016/j.cell.2018.03.032},
journal = {Cell},
number = 5,
volume = 173,
place = {United States},
year = {2018},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 49 works
Citation information provided by
Web of Science

Save / Share:

Works referencing / citing this record:

Structures, functions, and mechanisms of filament forming enzymes: a renaissance of enzyme filamentation
journal, November 2019


The molecular machinery of regulated cell death
journal, April 2019


The pathological features of regulated necrosis
journal, February 2019

  • Tonnus, Wulf; Meyer, Claudia; Paliege, Alexander
  • The Journal of Pathology, Vol. 247, Issue 5
  • DOI: 10.1002/path.5248

Microbial functional amyloids serve diverse purposes for structure, adhesion and defence
journal, May 2019


Pyroptosis versus necroptosis: similarities, differences, and crosstalk
journal, October 2018


The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations
journal, June 2019

  • Gelenter, Martin D.; Smith, Katelyn J.; Liao, Shu-Yu
  • Nature Structural & Molecular Biology, Vol. 26, Issue 7
  • DOI: 10.1038/s41594-019-0238-6

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant
journal, May 2019

  • Newell, Kathy; Paron, Francesca; Mompean, Miguel
  • Brain Pathology, Vol. 29, Issue 3
  • DOI: 10.1111/bpa.12680

Necroptosis: a crucial pathogenic mediator of human disease
journal, August 2019


Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform
journal, September 2019


Viral M45 and necroptosis‐associated proteins form heteromeric amyloid assemblies
journal, November 2018


Mimicry by a viral RHIM
journal, January 2019


Pannexin‐1 limits the production of proinflammatory cytokines during necroptosis
journal, August 2019

  • Douanne, Tiphaine; André‐Grégoire, Gwennan; Trillet, Kilian
  • EMBO reports, Vol. 20, Issue 10
  • DOI: 10.15252/embr.201947840