- Ras is a monomeric G protein (guanine nucleotide binding protein) with intrinsic GTPase activity.
- Its structure is related to the Gα subunit of the trimeric G protein.
- Ras proteins function as binary molecular switches that control intracellular signaling networks.
- Ras protein is a key component of receptor tyrosine kinase signaling cascade.
- Ras protein is anchored to the cytoplasmic side of the plasma membrane via lipid tails.
It can exist in 2 conformational states:
1) In the “off” state it is bound to the nucleotide guanosine diphosphate (GDP): Inactive for signaling
2) In the “on” state, Ras is bound to guanosine triphosphate (GTP): Active for signaling
- Ras is turned “on” by removing the GDP and replacing it with a GTP.
- In the GTP-bound conformation, Ras has a high affinity for numerous effectors which allow it to carry out its functions. These include PI3K,Raf etc.
The process of exchanging the bound nucleotide is facilitated by 2 proteins:
a) Guanine nucleotide exchange factors (GEFs)
- GEFs facilitate Ras activation by promoting GDP exchange to GTP
Example: Son of Sevenless (Sos), cdc 25 etc
b) GTPase activating proteins (GAPs)
- Intrinsic GTPase activity (self hydrolysis of the gamma phosphate of the bound GTP to GDP) of Ras protein is low. GAP accelerates the GTP hydrolysis by Ras.
- GTPase Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras inactivation
Both the exchange factors and GAPs are regulated by processes “upstream” of Ras that ultimately begin at the level of receptors in the cell membrane.
For example, when cells are stimulated there is an increase in the cellular level of the Ras · GTP complex. The active Ras · GTP complex binds to one or more “effector” molecules. This binding results on the signal being passed to “downstream” molecules and ultimately to transcription factors that alter the patterns of RNA expression in the nucleus.
Mutation in Ras-GAP gene causes neurofibromatosis 1.
These proteins are involved in the regulation of numerous processes, including cell division, differentiation, gene expression, cytoskeletal organization, vesicle trafficking, and nucleocytoplasmic transport.
Ras is mutated in 30% of human tumors. Most mutations block hydrolysis keeping Ras active and the cell in a proliferative state.