Volume 3 Article informations New insights into the roles of SMB domains in the ENPP1 protein Marwa Chourabi a,b,*, Pui Mun Wong a , Ali Saad b* Abstract ENPP1 (Ectonucleotide pyrophosphatase/phosphodiesterase 1) is a transmembrane enzyme with a short cytoplasmic region and a large extracellular domain consisting of two consecutive somatomedin (SMB) domains, a phosphodiesterase domain and a nuclease-like domain that lacks catalytic activity. It catalyzes the hydrolysis of ATP to AMP to produce extracellular inorganic pyrophosphate (PPi). By generating PPi, ENPP1 acts as a key regulator of tissue calcification and bone development. In humans, homozygous loss-of-function mutations in the phosphodiesterase domain and/or the nuclease domain of ENPP1 have been shown to cause several inherited disorders featuring either ectopic calcifications or abnormal calcium handling. While the catalytic domain of ENPP1 has been studied in some detail, the exact role of the two SMB domains remains unknown. This review aims to look behind the recent advances in our current understanding of the role of SMB domains in ENPP1 protein and outline for the first time the importance of these two domains in skin pigmentation. The SMB domains contain eight cysteine residues, each arranged in four disulphide bonds, and have been shown to mediate ENPP1 homo-dimerization through covalent cystine inter- and intra-molecular bonds. ENPP1 can inhibit insulin receptor autophosphorylation and downstream signaling through its SMB1 and SMB2 domains. Multiple mutations affecting conserved cysteines in the SMB domains have been identified to cause Cole disease, which is a rare skin pigmentation disorder. This interplay between ENPP1 and the insulin receptor may contribute to the pathogenesis of Cole disease and should be a future line of investigation. Key words: ENPP1, SMB domains, Cole disease, skin pigmentation