Title : Crystal
structure of Enpp1 , an extracellular
glycoprotein involved in bone mineralization and
insulin signaling
Abstract :
- Enpp1 is a membrane-bound glycoprotein that regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates to produce pyrophosphate
- Enpp1 dysfunction causes human diseases characterized by ectopic calcification
- Enpp1 also inhibits insulin signaling, and an Enpp1 polymorphism is associated with insulin resistance
- However, the precise mechanism by which Enpp1 functions in these cellular processes remains elusive
- Here, we report the crystal structures of the extracellular region of mouse Enpp1 in complex with four different nucleotide monophosphates, at resolutions of 2.7-3.2 Å
- The nucleotides are accommodated in a pocket formed by an insertion loop in the catalytic domain , explaining the preference of Enpp1 for an ATP substrate
- Structural mapping of disease-associated mutations indicated the functional importance of the interdomain interactions
- A structural comparison of Enpp1 with Enpp2 , a lysophospholipase D , revealed marked differences in the domain arrangements and active-site architectures
- Notably, the Enpp1 mutant lacking the insertion loop lost the nucleotide-hydrolyzing activity but instead gained the lysophospholipid-hydrolyzing activity of Enpp2
- Our findings provide structural insights into how the Enpp family proteins evolved to exert their diverse cellular functions