Title: Structural basis of substrate discrimination and integrin binding by autotaxin
Authors: Hausmann, Jens ×
Kamtekar, Satwik
Christodoulou, Evangelos
Day, Jacqueline E
Wu, Tao
Fulkerson, Zachary
Albers, Harald M H G
van Meeteren, Laurens A
Houben, Anna J S
van Zeijl, Leonie
Jansen, Silvia
Andries, Maria
Hall, Troii
Pegg, Lyle E
Benson, Timothy E
Kasiem, Mobien
Harlos, Karl
Kooi, Craig W Vander
Smyth, Susan S
Ovaa, Huib
Bollen, Mathieu
Morris, Andrew J
Moolenaar, Wouter H
Perrakis, Anastassis #
Issue Date: Feb-2011
Publisher: Nature Publishing Group
Series Title: Nature Structural and Molecular Biology vol:18 issue:2 pages:198-204
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.
ISSN: 1545-9993
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Biosignaling & Therapeutics
× corresponding author
# (joint) last author

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