Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency

The Journal of Biological Chemistry
Fernando Salgado-PoloAnastassis Perrakis

Abstract

Autotaxin (ATX) is a secreted glycoprotein and the only member of the ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses, such as cell migration, proliferation, and survival, implicating ATX-LPA signaling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, called the "pocket" and the "tunnel," respectively. However, the mechanisms in allosteric modulation of ATX's activity as a lysophospholipase D are unclear. Here, using the physiological LPC substrate, a new fluorescent substrate, and diverse ATX inhibitors, we revisited the kinetics and allosteric regulation of the ATX catalytic cycle, dissecting the different steps and pathways leading to LPC hydrolysis. We found that ATX activity is stimulated by LPA and that LPA activates ATX lysophospholipase D activity by binding to the ATX tunnel. A consolidation of all experimental kinetics data yielded a comprehensive catalytic model supported by molecular modeling simulations and suggested a positive feedback mechanism that is regulated by the abundance of t...Continue Reading

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Citations

Sep 27, 2020·International Journal of Molecular Sciences·Christiana MagkriotiVassilis Aidinis
Jun 12, 2020·Trends in Cardiovascular Medicine·Amer YoussefMichael B Boffa
Jul 11, 2021·Prostaglandins & Other Lipid Mediators·Toshihiko TsutsumiAkira Tokumura
Aug 4, 2021·Analytical Biochemistry·Celia DobersalskeFrank Wunder
Nov 28, 2021·Pharmaceuticals·Yi JiaHai Shang

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