The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis.

Published

Journal Article

RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of β-amyloids, as shown by Thioflavin T (ThT) and Congo red (CR) binding, circular dichroism, infrared spectroscopy, X-ray diffraction, and solid-state NMR. Structured amyloid cores are mapped in RIP1 and RIP3 that are flanked by regions of mobility. The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure, whereas necrosis is partially inhibited by ThT, CR, and another amyloid dye, HBX. Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. The current study provides insight into the structural changes that occur when RIP kinases are triggered to execute different signaling outcomes and expands the realm of amyloids to complex formation and signaling.

Full Text

Duke Authors

Cited Authors

  • Li, J; McQuade, T; Siemer, AB; Napetschnig, J; Moriwaki, K; Hsiao, Y-S; Damko, E; Moquin, D; Walz, T; McDermott, A; Chan, FK-M; Wu, H

Published Date

  • July 20, 2012

Published In

Volume / Issue

  • 150 / 2

Start / End Page

  • 339 - 350

PubMed ID

  • 22817896

Pubmed Central ID

  • 22817896

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.06.019

Language

  • eng

Conference Location

  • United States