小柯机器人

美国康涅狄格大学Wolfgang Peti等研究人员合作揭示PP2A:B55-FAM122A和PP2A:B55-ARPP19的冷冻电镜结构。相关论文于2023年12月20日在线发表于国际学术期刊《自然》。

研究人员报告了PP2A:B55与磷酸化ARPP19和FAM122A结合的单颗粒冷冻电镜结构。与核磁共振光谱互补研究相一致，这两种内在无序蛋白都与PP2A:B55结合，但结合方式非常不同，其利用了B55上多个不同的结合位点。大量的结构、生物物理和生物化学数据解释了底物和抑制剂是如何被招募到PP2A:B55上的，并为开发PP2A:B55相关疾病的治疗干预措施提供了分子路线图。

据了解，细胞周期的进展受磷酸化的调控。有丝分裂的进入是通过有丝分裂蛋白磷酸化的增加来启动的，这一过程由激酶驱动，而有丝分裂的退出则是通过抵消去磷酸化来实现的，这一过程由磷酸酶驱动，尤其是PP2A:B553。虽然激酶在有丝分裂进入过程中的作用已得到公认，但最近的数据表明，只有当平衡磷酸酶也受到抑制时，有丝分裂才能成功启动。PP2A:B55的抑制是由内在无序蛋白ARPP19和 FAM122A实现的。尽管它们在有丝分裂中起着关键作用，但它们实现PP2A:B55抑制的机制尚不清楚。

附：英文原文

Title: Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19

Author: Padi, Sathish K. R., Vos, Margaret R., Godek, Rachel J., Fuller, James R., Kruse, Thomas, Hein, Jamin B., Nilsson, Jakob, Kelker, Matthew S., Page, Rebecca, Peti, Wolfgang

Issue&Volume: 2023-12-20

Abstract: Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation1. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases2, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B553. Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited4. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP195,6 and FAM122A7. Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases.

DOI: 10.1038/s41586-023-06870-3

Source: https://www.nature.com/articles/s41586-023-06870-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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