Inorganic pyrophosphatases (PPases) catalyze the hydrolysis of pyrophosphate to phosphates. PPases play essential roles in growth and development, and are found in all kingdoms of life. Human possess two PPases, PPA1 and PPA2. PPA1 is present in all tissues, acting largely as a housekeeping enzyme. Besides pyrophosphate hydrolysis, PPA1 can also directly dephosphorylate phosphorylated c-Jun N-terminal kinases 1 (JNK1). Upregulated expression of PPA1 has been linked to many human malignant tumors. PPA1 knockdown induces apoptosis and decreases proliferation. PPA1 is emerging as a potential prognostic biomarker and target for anti-cancer drug development. In spite of the biological and physiopathological importance of PPA1, there is no detailed study on the structure and catalytic mechanisms of mammalian origin PPases. Here we report the crystal structure of human PPA1 at a resolution of 2.4 Å. We also carried out modeling studies of PPA1 in complex with JNK1 derived phosphor-peptides. The monomeric protein fold of PPA1 is similar to those found in other family I PPases. PPA1 forms a dimeric structure that should be conserved in animal and fungal PPases. Analysis of the PPA1 structure and comparison with available structures of PPases from lower organisms suggest that PPA1 has a largely pre-organized and relatively rigid active site for pyrophosphate hydrolysis. Results from the modeling study indicate the active site of PPA1 has the potential to accommodate double-phosphorylated peptides from JNK1. In short, results from the study provides new insights into the mechanisms of human PPA1 and basis for structure-based anti-cancer drug developments using PPA1 as the target.

中文翻译：

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人无机焦磷酸酶1的晶体学和模型研究：一种潜在的抗癌药物靶点

无机焦磷酸酶 (PPase) 催化焦磷酸水解为磷酸盐。PPase 在生长和发育中发挥重要作用，存在于所有生命王国中。人类拥有两种PPase，PPA1和PPA2。PPA1 存在于所有组织中，主要作为一种管家酶。除了焦磷酸水解，PPA1 还可以直接使磷酸化的 c-Jun N-末端激酶 1 (JNK1) 去磷酸化。PPA1 的上调表达与许多人类恶性肿瘤有关。PPA1 敲低诱导细胞凋亡并减少增殖。PPA1 正在成为一种潜在的预后生物标志物和抗癌药物开发的靶点。尽管 PPA1 具有生物学和生理病理学的重要性，但没有关于哺乳动物来源 PPases 的结构和催化机制的详细研究。在这里，我们以 2.4 Å 的分辨率报告人类 PPA1 的晶体结构。我们还对 PPA1 与 JNK1 衍生的磷肽复合物进行了建模研究。PPA1 的单体蛋白质折叠与其他家族 I PPases 中发现的相似。PPA1 形成一个二聚体结构，在动物和真菌 PPase 中应该是保守的。对 PPA1 结构的分析以及与来自低等生物的 PPases 的可用结构的比较表明，PPA1 具有一个很大程度上预先组织和相对刚性的焦磷酸水解活性位点。建模研究的结果表明 PPA1 的活性位点有可能容纳来自 JNK1 的双磷酸化肽。简而言之，