Structural basis of substrate discrimination and integrin binding by autotaxin
| Autor: | Lyle E. Pegg, Jens Hausmann, Harald M. H. G. Albers, Leonie van Zeijl, Karl Harlos, Wouter H. Moolenaar, Susan S. Smyth, Evangelos Christodoulou, Jacqueline E. Day, Craig W. Vander Kooi, Mobien Kasiem, Andrew J. Morris, Timothy E. Benson, Anna J. S. Houben, Anastassis Perrakis, Maria Andries, Zachary Fulkerson, Mathieu Bollen, Tao Wu, Silvia Jansen, Satwik Kamtekar, Troii Hall, Laurens A. van Meeteren, Huib Ovaa |
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| Rok vydání: | 2011 |
| Předmět: |
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 |
| Zdroj: | Nature Structural & Molecular Biology. 18:198-204 |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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