RIPK1:RIPK3 oligomerizes to form amyloid-like fibrils

Stable Identifier
R-HSA-5218905
Type
Reaction [transition]
Species
Homo sapiens
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Structural studies showed that activation of RIPK3 by RIPK1 involves the formation of a functional hetero-oligomeric amyloidal signaling complex that mediated programmed necrosis (Li J et al. 2012; Mompean M et al. 2018). The RIP homotypic interaction motifs (RHIMs) of RIPK1 and RIPK3 were found to mediate the assembly of these heterodimeric filamentous structures (Li J et al. 2012). RIPK1 was reported to control RIPK3 oligomerization in both postive and negative manners (Orozco S et al. 2014). RIPK3 recruitment to other RIPK3 protomers within this assembly may be favored by allosteric interactions between their kinase domains and activation by autophosphorylation of a site in the C-lobe of their kinase domains (Raju S et al. 2018). Presumably this autophosphorylation leads to an electrostatic repulsion or conformational change that disfavors RIPK3 hetero-oligomer formation to allow RIPK3 to preferentially self-associate within the necrosome complex. Owing to the size and the toxicity arising from overexpressing RIPK1 and RIPK3 in cells, this has been problematic to study in detail. The underlying mechanism is still debated, but RIPK3 transphosphorylation is believed to be crucial for MLKL activation (Orozco S et al. 2014; Cook WD et al. 2014).

Literature References
PubMed ID Title Journal Year
29681455 The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex

Bozkurt, G, Li, W, McDermott, AE, Wu, H, Mompeán, M, Li, J, Siemer, AB, Laage, S

Cell 2018
22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis

Hsiao, YS, McQuade, T, Wu, H, Chan, FK, Li, J, Walz, T, Siemer, AB, Moriwaki, K, McDermott, A, Moquin, D, Damko, E, Napetschnig, J

Cell 2012
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