Structural basis of substrate discrimination and integrin binding by autotaxin

Jens Hausmann, Satwik Kamtekar, Evangelos Christodoulou, Jacqueline E. Day, Tao Wu, Zachary Fulkerson, Harald M.H.G. Albers, Laurens A. Van Meeteren, Anna J.S. Houben, Leonie Van Zeijl, Silvia Jansen, Maria Andries, Troii Hall, Lyle E. Pegg, Timothy E. Benson, Mobien Kasiem, Karl Harlos, Craig W.Vander Kooi, Susan S. Smyth, Huib OvaaMathieu Bollen, Andrew J. Morris, Wouter H. Moolenaar, Anastassis Perrakis

Research output: Contribution to journalArticle

172 Scopus citations

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.

Original languageEnglish
Pages (from-to)198-205
Number of pages8
JournalNature Structural and Molecular Biology
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

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    Hausmann, J., Kamtekar, S., Christodoulou, E., Day, J. E., Wu, T., Fulkerson, Z., Albers, H. M. H. G., Van Meeteren, L. A., Houben, A. J. S., Van Zeijl, L., Jansen, S., Andries, M., Hall, T., Pegg, L. E., Benson, T. E., Kasiem, M., Harlos, K., Kooi, C. W. V., Smyth, S. S., ... Perrakis, A. (2011). Structural basis of substrate discrimination and integrin binding by autotaxin. Nature Structural and Molecular Biology, 18(2), 198-205. https://doi.org/10.1038/nsmb.1980