Location, location, location: a crystal-clear view of autotaxin saturating LPA receptors

Abstract

The interaction of autotaxin with its substrates leads to the production of lysophosphatidic acids (LPA), bioactive lipids with an emerging prominent role in inflammation and cancer. Two papers in this issue tell the previously unknown story of autotaxin, from substrate discrimination to highly efficient local delivery of LPA to target receptors.

Figure 1

Model for substrate recognition by ATX, LPA production and local receptor supersaturation. The surface of an activated platelet is shown, with the cartoon of a cross-section through the ATX protein and with domains labeled (C, catalytic domain; N, nuclease-like domain). Nucleotides cannot bind the active site when phospholipid substrates are engaged. A hydrophobic pocket in ATX accommodates LPC acyl chains and allows substrate discrimination. A channel between the catalytic site and SMB1 likely binds and shuttles LPA products before local delivery to the target receptor. Interaction of the SMB2 domain from ATX with a β3 integrin on the surface of the platelet may induce a conformational change in ATX that facilitates local release of LPA product at the cognate GPCR. This would achieve a high local specific concentration of product at the receptor site, effectively supersaturating the receptor relative to the rest of the platelet microenvironment and eliciting intracellular downstream signals. A flat surface at the hydrophobic channel entrance facilitates local interfacing with the target cell membrane.