Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
Nat Commun. 2021 Nov 22;12(1):6783. doi: 10.1038/s41467-021-27032-x.
The ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL.
溶细胞性细胞死亡模式（坏死性凋亡）的祖先起源于宿主防御。然而，坏死性凋亡在炎症性疾病中的失调导致了人们对靶向该途径进行治疗的广泛关注。这种细胞死亡模式由终末效应子 MLKL 假激酶执行，该激酶在其上游调节因子 RIPK3 激酶磷酸化后被许可杀死。MLKL 激活的精确分子细节仍在不断出现，有趣的是，在物种之间似乎存在机制上的差异。在这里，我们报告了单独的人 RIPK3 激酶结构域及其与人 MLKL 假激酶的复合物结构。这些结构揭示了人 RIPK3 如何在结构上与其小鼠对应物不同，以及人 RIPK3 如何在诱导坏死性凋亡之前将 MLKL 保持在无活性构象。RIPK3:MLKL C lobe 界面内的残基对于复合物组装和人细胞中的坏死性信号传导至关重要，从而合理地解释了严格的种属特异性，即 RIPK3 对 MLKL 的激活。
