Title :
structure of NPP1 , an ectonucleotide
pyrophosphatase/phosphodiesterase involved in tissue calcification
Abstract :
- 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
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*Output_Site_Fusion* (sent_index,
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