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Guanine nucleotide exchange factors (GEFs) are components of intracellular signalling networks. They function as activators of small GTPases[1] (see Nucleotide exchange factor). G proteins function as molecular switches, where the resting (inactive) state they are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP), which exists at a approximate 10-fold higher concentration in the cell cytoplasm. 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.
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Regulation
The GEF activity of a given protein is provided by one or more protein domains. A tandem placement of a dbl homology (DH) domain followed by a pleckstrin homology (PH) domain forms 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 and catalytic activity. 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 hydrolysis of 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
- SOS (Son of Sevenless) - A GEF that is important in the cell growth-regulatory MAPK/ERK pathway. It is an activator of the small G protein Ras.
- DOCK (Dedicator of cytokinesis) - A family of related GEFs which are involved in regulating the cytoskeleton. Isoforms of this family are activators of the small G proteins Rac and Cdc42.
- 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 Rho family.
- 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 (Arabidopsis thaliana)
References
- ^ <href="http://pubmedcentralcanada.ca/articlerender.cgi?tool=pubmed&pubmedid=17934073">Clin Microbiol Rev. 2007 October; 20(4): 535–549. </href>
See also
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