title: The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis.
abstract: 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.
authors: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Jixi
authors: J
authors: Li
authors: Thomas
authors: T
authors: McQuade
authors: Ansgar B
authors: AB
authors: Siemer
authors: Johanna
authors: J
authors: Napetschnig
authors: Kenta
authors: K
authors: Moriwaki
authors: Yu-Shan
authors: YS
authors: Hsiao
authors: Ermelinda
authors: E
authors: Damko
authors: David
authors: D
authors: Moquin
authors: Thomas
authors: T
authors: Walz
authors: Ann
authors: A
authors: McDermott
authors: Francis Ka-Ming
authors: FK
authors: Chan
authors: Hao
authors: H
authors: Wu
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D009336:Necrosis / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D000682:Amyloid; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases