Question

Summarize the events learned in cell biology that utilize guanine nucleotide exchange molecular switches and illustrate how guanine nucleotide exchange functions in these events.

Answer 1

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains involved in the activation of small GTPases. Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets.

The mechanism of GTPase activation varies among different GEFs. However, there are some similarities in how different GEFs alter the conformation of the G protein nucleotide-binding site. GTPases contain two loops called switch 1 and switch 2 that are situated on either side of the bound nucleotide. These regions and the phosphate-binding loop of the GTPase interact with the phosphates of the nucleotide and a coordinating magnesium ion to maintain high affinity binding of the nucleotide. GEF binding induces conformational changes in the P loop and switch regions of the GTPase while the rest of the structure is largely unchanged. The binding of the GEF sterically hinders the magnesium-binding site and interferes with the phosphate-binding region, while the base-binding region remains accessible. When the GEF binds the GTPase, the phosphate groups are released first and the GEF is displaced upon binding of the entering GTP molecule. Though this general scheme is common among GEFs, the specific interactions between the regions of the GTPase and GEF vary among individual proteins.

Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins.They are activated by Rho Guanine nucleotide Exchange Factors (GEF), which accelerate the GDP to GTP exchange.