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09:14
Static Adhesion Assay for the Study of Integrin Activation in T Lymphocytes
Published on: June 13, 2014
Structural basis of substrate discrimination and integrin binding by autotaxin
Jens Hausmann1, Satwik Kamtekar, Evangelos Christodoulou
1Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nature Structural & Molecular Biology
|January 18, 2011
Summary
Autotaxin (ATX) generates lysophosphatidic acid (LPA), crucial in disease. This study reveals ATX
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Autotaxin (ATX, ENPP2) is a secreted enzyme generating lysophosphatidic acid (LPA).
- ATX-LPA signaling pathways are implicated in tumor progression and inflammation.
- The precise mechanisms of ATX substrate recognition, catalysis, and cell interaction remain largely undefined.
Purpose of the Study:
- To elucidate the molecular basis of substrate recognition and catalysis by Autotaxin (ATX).
- To investigate the mechanism of ATX interaction with target cells.
- To identify potential targets for small-molecule therapeutic agents against ATX.
Main Methods:
- Determined the crystal structure of Autotaxin (ATX), both alone and complexed with an inhibitor.
- Utilized structural data to identify key residues involved in catalysis and substrate specificity.
- Investigated ATX interactions with cell-surface integrins.
Main Results:
- Identified a hydrophobic lipid-binding pocket within ATX.
- Mapped critical residues responsible for catalysis and discrimination between nucleotide and phospholipid substrates.
- Revealed an atypical mechanism for ATX interaction with cell-surface integrins via its N-terminal domains.
Conclusions:
- Defined key determinants governing substrate discrimination within the ENPP enzyme family.
- Provided insights into how ATX facilitates localized LPA signaling.
- Suggested novel strategies for developing small-molecule therapeutics targeting ATX.
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