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Structural basis for substrate discrimination and integrin binding by autotaxin
Autotaxin (ATX) or ecto-nucleotide pyrophosphatase/phosphodiesterase-2 (ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemo-attractant for many cell types. ATX-LPA signaling has roles in various pathologies including tumour prog...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064516/ https://www.ncbi.nlm.nih.gov/pubmed/21240271 http://dx.doi.org/10.1038/nsmb.1980 |
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author | Hausmann, Jens Kamtekar, Satwik Christodoulou, Evangelos Day, Jacqueline E. Wu, Tao Fulkerson, Zachary Albers, Harald M.H.G. van Meeteren, Laurens A. Houben, Anna van Zeijl, Leonie Jansen, Silvia Andries, Maria Hall, Troii Pegg, Lyle E. Benson, Timothy E. Kasiem, Mobien Harlos, Karl Vander Kooi, Craig Smyth, Susan S. Ovaa, Huib Bollen, Mathieu Morris, Andrew J. Moolenaar, Wouter H. Perrakis, Anastassis |
author_facet | Hausmann, Jens Kamtekar, Satwik Christodoulou, Evangelos Day, Jacqueline E. Wu, Tao Fulkerson, Zachary Albers, Harald M.H.G. van Meeteren, Laurens A. Houben, Anna van Zeijl, Leonie Jansen, Silvia Andries, Maria Hall, Troii Pegg, Lyle E. Benson, Timothy E. Kasiem, Mobien Harlos, Karl Vander Kooi, Craig Smyth, Susan S. Ovaa, Huib Bollen, Mathieu Morris, Andrew J. Moolenaar, Wouter H. Perrakis, Anastassis |
author_sort | Hausmann, Jens |
collection | PubMed |
description | Autotaxin (ATX) or ecto-nucleotide pyrophosphatase/phosphodiesterase-2 (ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemo-attractant for many cell types. ATX-LPA signaling has roles in various pathologies including tumour progression and inflammation. However, the molecular basis of substrate recognition and catalysis, and the mechanism of interaction with target cells, has been elusive. Here we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We identify a hydrophobic lipid-binding pocket and map key residues required for catalysis and selection between nucleotide and phospholipid substrates. We show that ATX interacts with cell-surface integrins via 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 enable new approaches to target ATX with small-molecule therapeutics. |
format | Text |
id | pubmed-3064516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-30645162011-08-01 Structural basis for substrate discrimination and integrin binding by autotaxin Hausmann, Jens Kamtekar, Satwik Christodoulou, Evangelos Day, Jacqueline E. Wu, Tao Fulkerson, Zachary Albers, Harald M.H.G. van Meeteren, Laurens A. Houben, Anna van Zeijl, Leonie Jansen, Silvia Andries, Maria Hall, Troii Pegg, Lyle E. Benson, Timothy E. Kasiem, Mobien Harlos, Karl Vander Kooi, Craig Smyth, Susan S. Ovaa, Huib Bollen, Mathieu Morris, Andrew J. Moolenaar, Wouter H. Perrakis, Anastassis Nat Struct Mol Biol Article Autotaxin (ATX) or ecto-nucleotide pyrophosphatase/phosphodiesterase-2 (ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemo-attractant for many cell types. ATX-LPA signaling has roles in various pathologies including tumour progression and inflammation. However, the molecular basis of substrate recognition and catalysis, and the mechanism of interaction with target cells, has been elusive. Here we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We identify a hydrophobic lipid-binding pocket and map key residues required for catalysis and selection between nucleotide and phospholipid substrates. We show that ATX interacts with cell-surface integrins via 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 enable new approaches to target ATX with small-molecule therapeutics. 2011-01-16 2011-02 /pmc/articles/PMC3064516/ /pubmed/21240271 http://dx.doi.org/10.1038/nsmb.1980 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hausmann, Jens Kamtekar, Satwik Christodoulou, Evangelos Day, Jacqueline E. Wu, Tao Fulkerson, Zachary Albers, Harald M.H.G. van Meeteren, Laurens A. Houben, Anna van Zeijl, Leonie Jansen, Silvia Andries, Maria Hall, Troii Pegg, Lyle E. Benson, Timothy E. Kasiem, Mobien Harlos, Karl Vander Kooi, Craig Smyth, Susan S. Ovaa, Huib Bollen, Mathieu Morris, Andrew J. Moolenaar, Wouter H. Perrakis, Anastassis Structural basis for substrate discrimination and integrin binding by autotaxin |
title | Structural basis for substrate discrimination and integrin binding by autotaxin |
title_full | Structural basis for substrate discrimination and integrin binding by autotaxin |
title_fullStr | Structural basis for substrate discrimination and integrin binding by autotaxin |
title_full_unstemmed | Structural basis for substrate discrimination and integrin binding by autotaxin |
title_short | Structural basis for substrate discrimination and integrin binding by autotaxin |
title_sort | structural basis for substrate discrimination and integrin binding by autotaxin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064516/ https://www.ncbi.nlm.nih.gov/pubmed/21240271 http://dx.doi.org/10.1038/nsmb.1980 |
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