*3.4. NPP1 Structure*

NPP1 is a membrane bound enzyme consisting of 840 amino acids (just under 100 kDa) that belongs to the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. NPP1 is a type II transmembrane glycoprotein comprised of two identical disulfide-bonded subunits. The polypeptide has a short N-terminal cytoplasmic domain followed by a transmembrane region. The extracellular structure consists of two somatomedin B (SMB)-like domains (SMB1 and SMB2), a phosphodiesterase domain and a nuclease-like domain [84]. The SMB-like domains are disordered and do not interact with the catalytic domain. The mapping of disease-causing mutations highlights the functional significance of the interaction between the catalytic and nuclease-like domains. It is the SMB2 domain of NPP1 that interacts with the insulin receptor and carries out physiological functions other than the regulation of mineralization [85].
