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.
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; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Curr Opin Struct Biol. 2024 Oct;88:102891. doi: 10.1016/j.sbi.2024.102891. Epub 2024 Jul 25.
Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.
细胞程序性坏死是一种与炎症性疾病相关的细胞程序性死亡形式，其潜在机制和治疗前景引起了广泛关注。在此，我们综述了我们目前对细胞程序性坏死途径的终末执行者——坏死激酶样混合谱系激酶结构域（MLKL）如何被上游调节激酶 RIPK3 从休眠状态转变为杀伤状态的结构理解。RIPK3 介导的 MLKL 的假激酶结构域的磷酸化作用，触发了一个分子开关，导致 MLKL 与细胞质平台解离、形成 MLKL 寡聚体，并转运到质膜，在质膜上，激活的 MLKL 聚集并使脂双层通透以诱导细胞死亡。我们强调了 MLKL 激活的机制知识中的空白、不同物种之间机制的差异以及建模在推进结构见解方面的作用。
