Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues
Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues
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DOI：
10.1038/s41467-020-16823-3
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发表时间：
2020-06-19
影响因子：
16.6
通讯作者：
Murphy, James M.
中科院分区：
文献类型：
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作者：
Davies, Katherine A.;Fitzgibbon, Cheree;Murphy, James M.
MLKL假激酶是坏死性凋亡细胞死亡途径中的末端效应子。通过其上游调节因子RIPK 3的磷酸化，触发MLKL从休眠的细胞质蛋白转化为寡聚体，所述寡聚体移位到质膜并使质膜透化以杀死细胞。这些过程背后的确切机制尚不完全清楚，并且被认为在小鼠和人类细胞之间存在差异。在这里，我们研究了9种脊椎动物MLKL直系同源物之间激活机制的分歧，揭示了小鼠和人RIPK 3对MLKL直系同源物的显着特异性。猪MLKL可以恢复人细胞中的坏死性凋亡信号;而马和猪，但不是大鼠，MLKL可以重建小鼠通路。这种选择性可以从马和大鼠MLKL假激酶结构域的晶体结构中观察到的不同构象来合理化。这些研究确定了重要的差异，在necroptotic信号的物种之间，并建议，更广泛地说，不同的监管机制可能存在于orthopathic pseudoenzymes。坏死性凋亡细胞死亡途径涉及通过假激酶的信号传导。在这里，作者定义了由必需的坏死性效应假激酶，混合谱系激酶结构域样（MLKL）介导的坏死性凋亡信号传导中的物种特异性的结构决定因素。
The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL's conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes. The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).