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Structural basis of substrate discrimination and integrin binding by autotaxin
- Source :
- Nature Structural & Molecular Biology. 18:198-204
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
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.
- Subjects :
- 0303 health sciences
biology
Phosphatase
Integrin
Plasma protein binding
Lipid signaling
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
chemistry
Biochemistry
Structural Biology
030220 oncology & carcinogenesis
Lysophosphatidic acid
biology.protein
lipids (amino acids, peptides, and proteins)
Autotaxin
Binding site
Molecular Biology
030304 developmental biology
Integrin binding
Subjects
Details
- ISSN :
- 15459985 and 15459993
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Nature Structural & Molecular Biology
- Accession number :
- edsair.doi...........d0127ea71e1de23fd487334a953f7a46