Structural Biology

RhoGDI Provides a Rho Less Traveled

Science's STKE  22 Feb 2000:
Vol. 2000, Issue 20, pp. tw11
DOI: 10.1126/stke.2000.20.tw11

The Rho family of small GTPase proteins comprises Cdc42, Rac, and Rho. They are important for mediating actin reorganization and cell growth, and are essential for Ras-induced cellular transformation. Guanine nucleotide dissociation inhibitors (GDIs) antagonize Rho activity by blocking guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that normally regulate Rho proteins. GDIs also sequester Rho away from the plasma membrane. Hoffman et al. report the x-ray crystallographic structure of a RhoGDI/Cdc42 complex that may explain how RhoGDI is able to perform several means of inhibition. The first step in Cdc42 inhibition involves the NH2-terminal arm on RhoGDI that binds to the switch I and II domains of Cdc42, preventing GDP dissociation and GTP hydrolysis. This positions the geranylgeranyl-binding region on RhoGDI close to the inner leaflet of the plasma membrane near the geranylgeranyl moiety of Cdc42. Subsequently, this may allow the hydrophobic lipid to be relocated from the plasma membrane to the RhoGDI-binding pocket without contacting the hydrophilic cytoplasm. Rho proteins are thus relocated into the cytoplasm away from active signaling pathways.

Hoffman, G.R., Nassar, N., and Cerione, R.A. (2000) Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100: 345-356. [Online Journal]