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Title: Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification
Authors: Jansen, Silvia ×
Perrakis, Anastassis
Ulens, Chris
Winkler, Claudia
Andries, Maria
Joosten, Robbie P
Van Acker, Maarten
Luyten, Frank
Moolenaar, Wouter H
Bollen, Mathieu #
Issue Date: Nov-2012
Publisher: Current Biology
Series Title: Structure vol:20 issue:11 pages:1948-1959
Article number: S0969-2126(12)00330-9
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.
ISSN: 0969-2126
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Cell and Gene Therapy Applications (-)
Laboratory of Biosignaling & Therapeutics
× corresponding author
# (joint) last author

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