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Title: Structural basis of substrate discrimination and integrin binding by autotaxin

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.
Authors:
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  1. (Pfizer)
  2. (
Publication Date:
OSTI Identifier:
1023641
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nat. Struct. Mol. Biol.; Journal Volume: 18; Journal Issue: 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
AHANIH
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CATALYSIS; CRYSTAL STRUCTURE; DRUGS; INFLAMMATION; LIPIDS; MITOGENS; NEOPLASMS; NUCLEOTIDES; PHOSPHATASES; PHOSPHOLIPIDS; PHOSPHODIESTERASES; RESIDUES; SUBSTRATES; TARGETS