How to switch a master switch

Abstract

The crystal structure of a nucleotide exchange factor in white blood cells reveals an autoinhibitory mechanism that reinforces the switch-like behaviour of the signalling protein Ras.

Keywords: Human; cell signalling; diacylglycerol; nucleotide exchange factor.

Figure 1.

Ras cycles between a GTP-bound state (top; left panel) in which it interacts with downstream effector proteins, and a GDP-bound state (bottom) in which it is inactive. The activity of Ras is tightly regulated by many different proteins. However, it is also important for cells to control the activity of the proteins that deactivate Ras (called GAPs) and the proteins that activate Ras (called GEFs). RasGRP1 is a GEF: in its inactive conformation (bottom; right panel) it cannot bind to Ras because the binding site for Ras is blocked by a linker peptide (depicted in red) and because the C1 domains (depicted in dark blue) that recruit it to the membrane are buried within the RasGRP1 dimer. RasGRP1 can be activated by calcium ions and diacylglycerol binding to it: this removes the linker peptide and exposes the C1 domains (top; right panel).