RIPK1:RIPK3 oligomerizes to form amyloid-like fibrils

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).

结构研究揭示了RIPK1激活RIPK3的过程涉及形成一种功能性的异源寡聚淀粉样信号复合体，该复合体介导了程序性坏死（Li J 等人，2012；Mompean M 等人，2018）。研究发现，RIPK1和RIPK3的RIP同源相互作用基序（RHIMs）介导了这些异源二聚体丝状结构的组装（Li J 等人，2012）。RIPK1被报道以正负双向控制RIPK3寡聚化（Orozco S 等人，2014）。RIPK3在此组装中向其他RIPK3多聚体的募集可能得益于其激酶结构域之间的别构相互作用及其激酶结构域C叶中的位点自磷酸化激活（Raju S 等人，2018）。推测这种自磷酸化导致静电排斥或构象变化，不利于RIPK3异源寡聚体的形成，从而使得RIPK3在坏死复合体中选择性地自我关联。由于在细胞中过表达RIPK1和RIPK3会引发其大小和毒性，因此详细研究一直存在困难。其潜在机制尚存争议，但RIPK3的跨磷酸化被认为对MLKL的激活至关重要（Orozco S 等人，2014；Cook WD 等人，2014）。