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.
authors.affiliation: Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jansen
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
authors.forename: Claudia
authors.initials: C
authors.lastname: Winkler
authors.forename: Maria
authors.initials: M
authors.lastname: Andries
authors.forename: Robbie P
authors.initials: RP
authors.lastname: Joosten
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Acker
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
mesh_terms: D000595:Amino Acid Sequence; D002114:Calcinosis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011755:Pyrophosphatases / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases