Structural and biochemical characterization of autotaxin

Abstract

Autotaxin (ATX) was originally discovered as an __autocrine motility factor__ from melanoma cells, more than two decades ago, but its biochemical function remained elusive. It took another decade to show that ATX functions as a lysophospholipase D that generates the lipid growth factor lysophosphatidic acid LPA from lysophosphatidylcholine (LPC). It is now known that ATX is essential for embryonic development, while numerous studies associate the ATX-LPA signaling axis with various diseases, including cancer, fibrosis, neuropathic pain and immune-mediated diseases. As a serum-borne protein, ATX is easily accessible and due to its versatile enzymatic activities to generate various LPA species from different substrate precursors, an attractive target for therapeutic intervention; the number of ATX inhibitors is increasing steadily. The present thesis concerns the expression, purification, crystallization and chara cterization of the structure of ATX alone, and in complex with a small-molecule inhibitor (HA155).Furthermore the catalytic mechanism of ATX is described. These insights into the biology of ATX will help to accelerate the development of ATX inhibitors as therapeutic agents.