Title : Structural basis of substrate discrimination and integrin binding by
autotaxin
Abstract :
- Autotaxin ( ATX , also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2 ) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid ( LPA ), a mitogen and chemoattractant for many cell types
- ATX- LPA signaling is involved in various pathologies including tumor progression and inflammation
- However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear
- Here, we present the crystal structure of ATX , alone and in complex with a small-molecule inhibitor
- We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates
- We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains , using an atypical mechanism
- Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents