Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.,Nature Communications

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Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.
Nature Communications ( IF 14.7 ) Pub Date : 2019-01-31 , DOI: 10.1038/s41467-019-08393-w
Karen Ruiz ₁ , Tarjani M Thaker ₁ , Christopher Agnew ₁ , Lakshmi Miller-Vedam ₂ , Raphael Trenker ₁ , Clara Herrera ₃ , Maria Ingaramo ₄ , Daniel Toso ₅ , Adam Frost _{2,

5,

6} , Natalia Jura _{1,

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Affiliation

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

中文翻译：

PGAM5 多聚体组件的功能作用及其聚合成细丝。

PGAM5 是一种线粒体蛋白磷酸酶，其在小鼠中的基因消融会导致线粒体相关疾病，包括神经变性。PGAM5 的功能包括调节线粒体自噬、细胞死亡、新陈代谢和衰老。然而，人们对调节 PGAM5 激活和信号传导的机制知之甚少。使用电子冷冻显微镜，我们表明 PGAM5 在溶液中形成十二聚体。我们还展示了 PGAM5 的晶体结构，揭示了十二聚体形成的决定因素。此外，我们在体外和细胞中观察到 PGAM5 十二聚体组装成细丝。我们发现 PGAM5 寡聚化成十二聚体不仅对催化活化至关重要，而且这种形式还在线粒体膜上发挥结构作用，这与磷酸酶活性无关。一起，

更新日期：2019-01-31

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