Structural basis of substrate discrimination and integrin binding by autotaxin

Journal Article · Wed Sep 25 04:00:00 EDT 2013 · Nat. Struct. Mol. Biol.

DOI:https://doi.org/10.1038/nsmb.1980· OSTI ID:1023641

Hausmann, Jens; Kamtekar, Satwik; Christodoulou, Evangelos; Day, Jacqueline E.; Wu, Tao; Fulkerson, Zachary; 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; Vander Kooi, Craig W.; Smyth, Susan S.; Ovaa, Huib; Bollen, Mathieu ; Morris, Andrew J.; Moolenaar, Wouter H.; Perrakis, Anastassis ^[1]

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1. Pfizer

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: AHANIH
• OSTI ID: 1023641
• Journal Information: Nat. Struct. Mol. Biol., Journal Name: Nat. Struct. Mol. Biol. Journal Issue: 2011 Vol. 18
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CATALYSIS
CRYSTAL STRUCTURE
DRUGS
INFLAMMATION
LIPIDS
MITOGENS
NEOPLASMS
NUCLEOTIDES
PHOSPHATASES
PHOSPHODIESTERASES
PHOSPHOLIPIDS
RESIDUES
SUBSTRATES
TARGETS