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

Journal Article · · Cell
 [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)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH); National Science Foundation (NSF); National Key Research and Development Program of China; National Natural Science Foundation of China (NSFC)
Grant/Contract Number:
R01 AI045937; MCB 0749381; MCB 1412253; 2016YFA0500600; 31670878
OSTI ID:
1438888
Journal Information:
Cell, Vol. 173, Issue 5; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 187 works
Citation information provided by
Web of Science

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Cited By (18)

Pannexin‐1 limits the production of proinflammatory cytokines during necroptosis journal August 2019
The molecular machinery of regulated cell death journal April 2019
Microbial functional amyloids serve diverse purposes for structure, adhesion and defence journal May 2019
Viral M45 and necroptosis‐associated proteins form heteromeric amyloid assemblies journal November 2018
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
Structures, functions, and mechanisms of filament forming enzymes: a renaissance of enzyme filamentation journal November 2019
The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations journal June 2019
Mimicry by a viral RHIM journal January 2019
An Efficient, Robust New Scheme for Establishing Broadband Homonuclear Correlations in Biomolecular Solid State NMR journal January 2020
Pyroptosis versus necroptosis: similarities, differences, and crosstalk journal October 2018
The pathological features of regulated necrosis journal February 2019
Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant journal May 2019
SSNMR Structure of the Human RIP1/RIP3 Necrosome dataset January 2018
Life, death, and autophagy in cancer: NF-κB turns up everywhere journal March 2020
The molecular machinery of regulated cell death journal April 2019
Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform journal September 2019
Electrochemotherapy Causes Caspase-Independent Necrotic-Like Death in Pancreatic Cancer Cells journal August 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
SSNMR
solid state NMR
NMR structure
hetero-amyloid
functional amyloid
RHIM
RIPK1
RIPK3
signaling complex
X-ray crystallography