Guanine nucleotide exchange factor
Guanine nucleotide exchange factors (GEFs) are components of
intracellularsignalling networks. They function as activators of small GTPases(see Nucleotide exchange factor). In their resting state, G proteins are bound to Guanosine diphosphate(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate(GTP). GEFs activate G proteins by promoting this nucleotide exchange. The hundreds of GEFs described thus far exhibit varying degrees of specificity with some being able to activate multiple G proteins of different families and others only able to activate one specific isoform.
The GEF activity of a given protein is the result of one or more discrete domains. A tandem placement of a dbl homology (DH) domain followed by a
pleckstrin homology(PH) domain form the minimal functional unit of most GEFs (those of the dbl family). Specifically, the DH domain is the catalytic site required for GDP-GTP exchange, while the PH domain contributes to protein-protein, protein-cytoskeleton and protein-lipid interactions to help regulate the GEF's intracellular localization. Other accessory/regulatory domains are usually present in the protein displaying complimentary, inhibitory or unrelated functions. GEF domains can be found in a variety of signaling proteins, many of which are unrelated with respect to structure and physiological function.
GEF-dependent signaling is antagonized by
GTPase activating proteins (GAPs), which promote hydrolysisof GTP back to GDP and thus terminate GEF-G protein-mediated signaling events. Guanosine nucleotide dissociation inhibitors(GDIs) also antagonize GEFs by maintaining small GTPases in their GDP bound form, in addition to preventing the protein's association to the plasma membrane.
Examples of GEFs
*Vav - A small family of GEFs which have diverse cellular roles and have been shown to exhibit functions independent of their GEF activity. This family are activators of small G proteins of the
eIF-2b - The eukaryotic initiation factor 2b regenerates eIF-2a for an additional cycle in protein synthesis initiation, i.e., its binding to the Met-t-RNA.
G protein-coupled receptors function as GEFs for their cognate G proteins.
* GNOM ("
nucleotide exchange factor
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