Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification
Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification
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DOI：
10.1016/j.str.2012.09.001
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发表时间：
2012-11-07
期刊：
影响因子：
5.7
通讯作者：
Bollen, Mathieu
中科院分区：
文献类型：
--
作者：
Jansen, Silvia;Perrakis, Anastassis;Bollen, Mathieu
外核苷酸焦磷酸酶/磷酸二酯酶-1 (NPP1) 将细胞外核苷酸转化为无机焦磷酸盐，而其近亲 NPP2/自分泌运动因子则水解溶血磷脂。 NPP1 调节有矿化能力的组织中的钙化，NPP1 功能的缺乏是钙化疾病的基础。在这里，我们发现 NPP1 通过膜内二硫键形成同二聚体，但也在细胞内加工成分泌的单体。分泌型 NPP1 的结构揭示了特征性的双金属活性位点和核苷酸结合凹槽，但它缺乏 NPP2 中存在的脂质结合袋和开放通道。与核苷酸结合位点相邻的环在 NPP2 中是无序的，但在 NPP1 中是有序的，可能会促进核苷酸结合。值得注意的是，NPP1 的 N 端生长调节素 B 样结构域与 NPP2 中的结构域不同，是灵活的并且不接触催化结构域。我们的结果为 NPP1 的核苷酸焦磷酸酶活性提供了结构基础，并有助于了解致病突变如何影响 NPP1 的结构和功能。
Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative NPP2/autotaxin hydrolyzes lysophospholipids. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a secreted monomer. The structure of secreted NPP1 reveals a characteristic bimetallic active site and a nucleotide-binding groove, but it lacks the lipid-binding pocket and open tunnel present in NPP2. A loop adjacent to the nucleotide-binding site, which is disordered in NPP2, is well ordered in NPP1 and might promote nucleotide binding. Remarkably, the N-terminal somatomedin B-like domains of NPP1, unlike those in NPP2, are flexible and do not contact the catalytic domain. Our results provide a structural basis for the nucleotide pyrophosphatase activity of NPP1 and help to understand how disease-causing mutations may affect NPP1 structure and function.