Rac1 C Terminus Contributes to Effector Binding♦

Members of the Ras family of G proteins act as key switches in signal transduction pathways through their binding and activation of effector proteins. The G protein Rac1, for example, activates protein kinase C-related kinase 1 (PRK1), a critical regulator of the cytoskeletal network as well as other diverse processes.

Interaction of the polybasic region (blue) of Rac1 (purple) with PRK1 (green) does not disrupt membrane anchoring.

In this Paper of the Week, Rakhee Modha and colleagues have determined the structure Rac1 in complex with its effector PRK1, with a twist. The Rac1 crystal structure, unlike those of most G proteins, was solved with its membrane-anchoring C-terminal region intact. The structure revealed that the Rac1 C terminus reverses direction to interact with residues in the G protein core, whereas the polybasic region of the C terminus in fact interacts directly with the HR1b domain of PRK1. These interactions, however, do not hinder the ability of the polybasic region to interact with negatively charged phospholipids to tether Rac1 to the cell membrane. This study provides the first structural demonstration that the C terminus of a G protein forms an important recognition element for effector binding and could have profound implications for Rac1-mediated signal transduction.