PMID: 23041369

 

    Legend: Sugar

Title : structure of NPP1 , an ectonucleotide pyrophosphatase/phosphodiesterase involved in tissue calcification

Abstract :

1. Ectonucleotide pyrophosphatase/phosphodiesterase-1 ( NPP1 ) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative  NPP2 / autotaxin hydrolyzes lysophospholipids
2. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders
3. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a secreted monomer
4. 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
5. A loop adjacent to the nucleotide-binding site , which is disordered in NPP2 , is well ordered in NPP1 and might promote nucleotide binding
6. Remarkably, the N-terminal somatomedin B-like domains of NPP1 , unlike those in NPP2 , are flexible and do not contact the catalytic domain
7. 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