Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity.
Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity.
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DOI：
10.1016/j.jbc.2021.101526
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Perrakis A
中科院分区：
文献类型：
--
作者：
Borza R;Salgado-Polo F;Moolenaar WH;Perrakis A
外核苷酸焦磷酸/磷酸二酯酶家族成员(ENPP1-7)参与了许多重要的生物学和病理生理过程，包括核苷酸和磷脂信号转导、骨矿化、纤维化疾病和肿瘤相关免疫细胞的侵袭。ENPPs是一种单程跨膜外切酶，ENPP2和ENNP6是明显的例外，它们分别是分泌的和糖基磷脂酰肌醇(GPI)锚定的。ENNP1和ENNP2是特征最好、功能最有趣的成员。在这里，我们回顾了ENPP1-7的结构特征，以了解它们是如何进化来适应特定底物和调节不同的生物活性的。ENPPs是由保守的磷酸二酯酶(PDE)结构域定义的。在ENPP1-3中，PDE结构域两侧有两个N端的生长激素B样结构域和一个C端具有结构稳定性的非活性核酸酶结构域，而ENPP4-7只具有PDE结构域。底物结合部位的结构差异赋予了每种蛋白质独特的特征。因此，ENPP1、ENPP3、ENPP4和ENPP5可以水解核苷酸，而ENPP2、ENPP6和ENNP7则通过催化区域的适配进化为磷脂酶。这些适应解释了个体成员不同的生物学和病理生理功能。将ENPP成员作为一个整体了解有助于我们深入了解共同的机制，突出它们的功能多样性，并有助于探索新的生物角色。
Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family members (ENPP1–7) have been implicated in key biological and pathophysiological processes, including nucleotide and phospholipid signaling, bone mineralization, fibrotic diseases, and tumor-associated immune cell infiltration. ENPPs are single-pass transmembrane ecto-enzymes, with notable exceptions of ENPP2 (Autotaxin) and ENNP6, which are secreted and glycosylphosphatidylinositol (GPI)-anchored, respectively. ENNP1 and ENNP2 are the best characterized and functionally the most interesting members. Here, we review the structural features of ENPP1–7 to understand how they evolved to accommodate specific substrates and mediate different biological activities. ENPPs are defined by a conserved phosphodiesterase (PDE) domain. In ENPP1–3, the PDE domain is flanked by two N-terminal somatomedin B-like domains and a C-terminal inactive nuclease domain that confers structural stability, whereas ENPP4–7 only possess the PDE domain. Structural differences in the substrate-binding site endow each protein with unique characteristics. Thus, ENPP1, ENPP3, ENPP4, and ENPP5 hydrolyze nucleotides, whereas ENPP2, ENPP6, and ENNP7 evolved as phospholipases through adaptions in the catalytic domain. These adaptations explain the different biological and pathophysiological functions of individual members. Understanding the ENPP members as a whole advances our insights into common mechanisms, highlights their functional diversity, and helps to explore new biological roles.
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发表时间：
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影响因子：
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作者：
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