TY - JOUR
T1 - Structural basis of substrate discrimination and integrin binding by autotaxin
AU - Hausmann, Jens
AU - Kamtekar, Satwik
AU - Christodoulou, Evangelos
AU - Day, Jacqueline E.
AU - Wu, Tao
AU - Fulkerson, Zachary
AU - Albers, Harald M.H.G.
AU - Van Meeteren, Laurens A.
AU - Houben, Anna J.S.
AU - Van Zeijl, Leonie
AU - Jansen, Silvia
AU - Andries, Maria
AU - Hall, Troii
AU - Pegg, Lyle E.
AU - Benson, Timothy E.
AU - Kasiem, Mobien
AU - Harlos, Karl
AU - Kooi, Craig W.Vander
AU - Smyth, Susan S.
AU - Ovaa, Huib
AU - Bollen, Mathieu
AU - Morris, Andrew J.
AU - Moolenaar, Wouter H.
AU - Perrakis, Anastassis
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
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U2 - 10.1038/nsmb.1980
DO - 10.1038/nsmb.1980
M3 - Article
C2 - 21240271
AN - SCOPUS:79551636074
SN - 1545-9993
VL - 18
SP - 198
EP - 205
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -