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

Miguel Mompeán, Wenbo Li, Jixi Li, Ségolène Laage, Ansgar B. Siemer, Gunes Bozkurt, Hao Wu, Ann E. McDermott

Research output: Contribution to journalArticlepeer-review

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. 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. Solid-state NMR structures of the human necroptosis RIPK1-RIPK3 complex reveal a hetero-oligomeric amyloid signaling complex.

Original languageEnglish (US)
Pages (from-to)1244-1253.e10
JournalCell
Volume173
Issue number5
DOIs
StatePublished - May 17 2018

Keywords

  • NMR structure
  • RHIM
  • RIPK1
  • RIPK3
  • SSNMR
  • X-ray crystallography
  • functional amyloid
  • hetero-amyloid
  • signaling complex
  • solid state NMR

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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