Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Current opinion in structural biology Pub Date : 2024-07-25 DOI:10.1016/j.sbi.2024.102891
Katherine A. Davies , Peter E. Czabotar , James M. Murphy
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Abstract

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.

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葬礼上的死亡激活死亡酶 MLKL,通过坏死作用杀死细胞。
坏死是程序性细胞死亡的一种溶解形式,与炎症性病变有关,因此人们对其潜在机制和治疗前景产生了浓厚的兴趣。在此,我们回顾了我们目前对这一途径的终端执行者--死亡激酶混合系激酶结构域样(MLKL)如何通过上游调节激酶 RIPK3 从休眠状态转化为杀伤形式的结构性理解。RIPK3 介导的 MLKL 伪激酶结构域磷酸化会触发一个分子开关,诱导 MLKL 从细胞质平台解离,组装成 MLKL 寡聚体,并贩运到质膜,活化的 MLKL 在质膜上聚集并渗透脂质双分子层,从而诱导细胞死亡。我们强调了 MLKL 激活机理知识方面的差距、不同物种之间的机理差异以及建模在推进结构洞察力方面的力量。
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来源期刊
Current opinion in structural biology
Current opinion in structural biology 生物-生化与分子生物学
CiteScore
12.20
自引率
2.90%
发文量
179
审稿时长
6-12 weeks
期刊介绍: Current Opinion in Structural Biology (COSB) aims to stimulate scientifically grounded, interdisciplinary, multi-scale debate and exchange of ideas. It contains polished, concise and timely reviews and opinions, with particular emphasis on those articles published in the past two years. In addition to describing recent trends, the authors are encouraged to give their subjective opinion of the topics discussed. In COSB, we help the reader by providing in a systematic manner: 1. The views of experts on current advances in their field in a clear and readable form. 2. Evaluations of the most interesting papers, annotated by experts, from the great wealth of original publications. [...] The subject of Structural Biology is divided into twelve themed sections, each of which is reviewed once a year. Each issue contains two sections, and the amount of space devoted to each section is related to its importance. -Folding and Binding- Nucleic acids and their protein complexes- Macromolecular Machines- Theory and Simulation- Sequences and Topology- New constructs and expression of proteins- Membranes- Engineering and Design- Carbohydrate-protein interactions and glycosylation- Biophysical and molecular biological methods- Multi-protein assemblies in signalling- Catalysis and Regulation
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