Abstract
Localization of Ras and Ras-like proteins to the correct subcellular compartment is essential for these proteins to mediate their biological effects. Many members of the Ras superfamily (Ha-Ras, N-Ras, TC21, and RhoA) are prenylated in the cytoplasm and then transit through the endomembrane system on their way to the plasma membrane. The proteins that aid in the trafficking of the small GTPases have not been well characterized. We report here that prenylated Rab acceptor protein (PRA1), which others previously identified as a prenylation-dependent receptor for Rab proteins, also interacts with Ha-Ras, RhoA, TC21, and Rap1a. The interaction of these small GTPases with PRA1 requires their post-translational modification by prenylation. The prenylation-dependent association of PRA1 with multiple GTPases is conserved in evolution; the yeast PRA1 protein associates with both Ha-Ras and RhoA. Earlier studies reported the presence of PRA1 in the Golgi, and we show here that PRA1 co-localizes with Ha-Ras and RhoA in the Golgi compartment. We suggest that PRA1 acts as an escort protein for small GTPases by binding to the hydrophobic isoprenoid moieties of the small GTPases and facilitates their trafficking through the endomembrane system.
Highlights
The biological activity of Ras proteins is controlled by a regulated GTP/GDP cycle [2]
We demonstrate in this report that one of these proteins, Rip69, interacts with multiple members of the Ras superfamily, including Ha-Ras, RhoA, and TC21, and that the interaction of Rip69 with the small GTPases requires their post-translational modification by prenylation
In addition to interacting with Ha-Ras, PRA1 interacts with TC21 and RhoA, Fig. 1. These results indicate that the interaction of PRA1 with small GTPases is not specific to Rab proteins; instead, PRA1 interacts with multiple members of the Ras superfamily, including Ha-Ras, RhoA, and TC21
Summary
We report here that prenylated Rab acceptor protein (PRA1), which others previously identified as a prenylation-dependent receptor for Rab proteins, interacts with Ha-Ras, RhoA, TC21, and Rap1a The interaction of these small GTPases with PRA1 requires their post-translational modification by prenylation. Membrane localization of Ras creates a docking site for effectors, including the Raf kinases and phosphatidylinositol stimulator; ER, endoplasmic reticulum; GDI1, guanine nucleotide dissociation inhibitor 1; GST, glutathione S-transferase; PRA1, prenylated Rab acceptor protein; SOS, son of sevenless; GFP, green fluorescent protein; eGFP, enhanced GFP; PCR, polymerase chain reaction; IP, immunoprecipitation. We demonstrate in this report that one of these proteins, Rip, interacts with multiple members of the Ras superfamily, including Ha-Ras, RhoA, and TC21, and that the interaction of Rip with the small GTPases requires their post-translational modification by prenylation. PRA1 is predicted to play a conserved role in the biology of small GTPases in all eukaryotic cells
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