Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94158, USA.
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, 94158, USA.
Nat Commun. 2019 Jan 31;10(1):531. doi: 10.1038/s41467-019-08393-w.
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.
PGAM5 是一种线粒体蛋白磷酸酶，其在小鼠中的基因缺失会导致与线粒体相关的疾病，包括神经退行性变。PGAM5 的功能包括调节线粒体自噬、细胞死亡、代谢和衰老。然而，调节 PGAM5 激活和信号转导的机制还知之甚少。我们使用电子冷冻显微镜显示 PGAM5 在溶液中形成十二聚体。我们还呈现了 PGAM5 的晶体结构，揭示了十二聚体形成的决定因素。此外，我们观察到 PGAM5 十二聚体在体外和细胞内组装成纤维。我们发现，PGAM5 寡聚化为十二聚体不仅对催化激活至关重要，而且这种形式在质膜上也发挥结构作用，而不依赖于磷酸酶活性。总之，这些发现表明，调节 PGAM5 的寡聚化可能是一种具有潜在治疗意义的调节开关。
