Fig. 1: Fibril formation cascade in necroptotic signaling. | Nature Communications

Fig. 1: Fibril formation cascade in necroptotic signaling.

From: Structural basis for amyloid fibril assembly by the master cell-signaling regulator receptor-interacting protein kinase 1

Fig. 1

Schematic of the stepwise assembly of RHIM-containing proteins into amyloidogenic complexes named “necrosomes” during necroptosis. In the canonical pathway, tumor necrosis factor receptor 1 (TNFR1) stimulation promotes RIPK1 self-association and activation. Activated RIPK1 nucleates the formation of a heteromeric RIPK1–RIPK3 amyloid, which subsequently seeds homomeric RIPK3 fibrils. These RIPK3 fibrils then recruit MLKL to drive membrane permeabilization and execute necroptosis. The ZBP1-dependent pathway is included as an example of non-canonical necroptosis initiated by Z-DNA recognition. In this case, ZBP1 engages RIPK1 through RHIM–RHIM interactions, enabling the formation of a heteromeric complex with RIPK3 that again triggers RIPK3 homomeric assembly and MLKL oligomerization. Domain annotations are indicated in the legend at the upper-right corner. RHIM RIP homotypic interaction motif KD kinase domain, DD death domain, Zα Z-nucleic acid-binding domain, HBD helical bundle domain, PsKD pseudokinase domain. RHIM motifs are aligned vertically when engaged in RHIM–RHIM contacts. Arrows indicate the proposed sequence of events supported by structural and biochemical evidence.

Back to article page