Sphingosine kinase: a closer look at last

Abstract

Sphingosine-1-phosphate is a potent sphingolipid mediator, and the kinase that produces it, sphingosine kinase 1 (SphK1), has been implicated in cancer progression, inflammation, and cardiovascular diseases. In this issue of Structure, Wang and colleagues provide the scientific community with the long awaited structure of SphK1.

Figure 1

In the unbound state (top left), SphK1 has two openings (colored blue) through which the sphingosine substrate can enter the ligand cavity (colored green). In the sphingosine (colored yellow) bound state (top right), conformational rearrangements of the opening occlude access to cavity residues. The J-shaped ligand cavity (not shown) is lined with non-polar residues that help guide sphingosine by a head-to-tail tunneling mechanism (Wang et al., 2013; inset, bottom right). However, in cells, sphingosine (inset, colored yellow) is likely embedded with other membrane lipids such as phosphatydylcholine (inset, colored cpk), and little is known regarding how SphK1 recognizes, binds, and extracts sphingosine from membranes.