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Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric
GTPases GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
by stimulating the release of
guanosine diphosphate Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine. GDP is the pr ...
(GDP) to allow binding of
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only di ...
(GTP). A variety of unrelated
structural domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
s have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.


Function

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains involved in the activation of
small GTPases Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrim ...
. Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets. The most well-known GTPases comprise the
Ras superfamily The Ras superfamily, derived from "Rat sarcoma virus", is a protein superfamily of small GTPases. Members of the superfamily are divided into families and subfamilies based on their structure, sequence and function. The five main families are Ra ...
and are involved in essential cell processes such as cell differentiation and proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport. GTPases are active when bound to GTP and inactive when bound to GDP, allowing their activity to be regulated by GEFs and the opposing GTPase activating proteins (GAPs). GDP dissociates from inactive GTPases very slowly. The binding of GEFs to their GTPase substrates catalyzes the dissociation of GDP, allowing a GTP molecule to bind in its place. GEFs function to promote the dissociation of GDP. After GDP has disassociated from the GTPase, GTP generally binds in its place, as the cytosolic ratio of GTP is much higher than GDP at 10:1. The binding of GTP to the GTPase results in the release of the GEF, which can then activate a new GTPase. Thus, GEFs both destabilize the GTPase interaction with GDP and stabilize the nucleotide-free GTPase until a GTP molecule binds to it. GAPs (GTPase-activating protein) act antagonistically to inactivate GTPases by increasing their intrinsic rate of GTP hydrolysis. GDP remains bound to the inactive GTPase until a GEF binds and stimulates its release. The localization of GEFs can determine where in the cell a particular GTPase will be active. For example, the
Ran RAN may refer to: * Radio access network, a part of a mobile telecommunication system * Rainforest Action Network * Ran (gene) (RAs-related Nuclear protein), also known as GTP-binding nuclear protein Ran, a protein that in humans is encoded by t ...
GEF,
RCC1 Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein. RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase. Interactions ...
, is present in the nucleus while the Ran GAP is present in the cytosol, modulating nuclear import and export of proteins. RCC1 converts RanGDP to RanGTP in the nucleus, activating Ran for the export of proteins. When the Ran GAP catalyzes conversion of RanGTP to RanGDP in the cytosol, the protein cargo is released.


Mechanism

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 Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
-binding loop of the GTPase interact with the phosphates of the nucleotide and a coordinating
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
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.


Structure and specificity

Some GEFs are specific to a single GTPase while others have multiple GTPase substrates. While different subfamilies of Ras superfamily GTPases have a conserved GTP binding domain, this is not the case for GEFs. Different families of GEFs correspond to different Ras subfamilies. The functional domains of these GEF families are not structurally related and do not share sequence homology. These GEF domains appear to be evolutionarily unrelated despite similar function and substrates.


CDC25 domain

The CDC25 homology domain, also called the
RasGEF domain RasGEF domain is domain found in the CDC25 Protein family, family of guanine nucleotide exchange factors for Ras superfamily, Ras-like small GTPases. Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydro ...
, is the catalytic domain of many Ras GEFs, which activate Ras GTPases. The CDC25 domain comprises approximately 500 amino acids and was first identified in the CDC25 protein in budding yeast (''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
)''.


DH and PH domains

Dbl-like RhoGEFs were present at the origin of eukaryotes and evolved as highly adaptive cell signaling mediators. Dbl-like RhoGEFs are characterized by the presence of a Dbl Homology domain (
DH domain RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF ...
), responsible for GEF catalytic activity for
Rho GTPases #REDIRECTRho family of GTPases The Rho family of GTPases is a family of small (~21 kDa) signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular ...
. The human genome encodes 71 members, distributed into 20 subfamilies. All 71 members were already present in early Vertebrates, and most of the 20 subfamilies were already present in early Metazoans. Many of the mammalian Dbl family proteins are tissue-specific and their number in Metazoa varies in proportion of cell signaling complexity.
Pleckstrin homology domain Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...
s (
PH domain Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...
s) are associated in tandem with
DH domain RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF ...
s in 64 of the 71 Dbl family members. The PH domain is located immediately adjacent to the C terminus of the DH domain. Together, these two domains constitute the minimum structural unit necessary for the activity of most Dbl family proteins. The PH domain is involved in intracellular targeting of the DH domain. It is generally thought to modulate membrane binding through interactions with phospholipids, but its function has been shown to vary in different proteins. This PH domain is also present in other proteins beyond RhoGEFs.


DHR2 domain

The
DHR2 domain DHR2 (DOCK homology region 2), also known as CZH2 or Docker2, is a protein domain of approximately 450-550 amino acids that is present in the DOCK family of proteins. This domain functions as a guanine nucleotide exchange factor (GEF) domain for sm ...
is the catalytic domain of the DOCK family of Rho GEFs. Like
DH domain RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF ...
, DHR2 was already present at the origin of eukaryotes. The DOCK family is a separate subset of GEFs from the Dbl family and bears no structural or sequence relation to the DH domain. There are 11 identified DOCK family members divided into subfamilies based on their activation of
Rac RAC or Rac may refer to: Organizations * Radio Amateurs of Canada * RATCH-Australia Corporation, electricity generator * Refugee Action Collective (Victoria), Melbourne, Australia * Religious Action Center of Reform Judaism, US * Rent-A-Cent ...
and
Cdc42 Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...
. DOCK family members are involved in cell migration, morphogenesis and phagocytosis. The DHR2 domain is approximately 400 amino acids. These proteins also contain a second conserved domain, DHR1, which is approximately 250 amino acids. The DHR1 domain been shown to be involved in the membrane localization of some GEFs.


Sec7 domain

The Sec7 domain is responsible for the GEF catalytic activity in
ARF GTPase ARF may refer to: Organizations * Advertising Research Foundation * Animal Rescue Foundation * Armenian Revolutionary Federation * ASEAN Regional Forum People * Cahit Arf (1910–1997), Turkish mathematician Science, medicine, and mathematics ...
s. ARF proteins function in
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features ...
trafficking. Though ARF GEFs are divergent in their overall sequences, they contain a conserved Sec 7 domain. This 200 amino acid region is homologous to the yeast Sec7p protein.


Regulation

GEFs are often recruited by adaptor proteins in response to upstream signals. GEFs are multi-domain proteins and interact with other proteins inside the cell through these domains. Adaptor proteins can modulate GEF activity by interacting with other domains besides the catalytic domain. For example,
SOS SOS is a Morse code distress signal (), used internationally, originally established for maritime use. In formal notation SOS is written with an overscore line (), to indicate that the Morse code equivalents for the individual letters of "SOS" a ...
1, the Ras GEF in the
MAPK/ERK pathway The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell (biology), cell that communicates a signal from a Receptor (biochemistry), receptor on the surface of the cell to the DNA in the nucleus of the cel ...
, is recruited by the adaptor protein
GRB2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...
in response to
EGF receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...
activation. The binding of SOS1 to GRB2 localizes it to the plasma membrane, where it can activate the membrane-bound Ras. Other GEFs, such as the
Rho Rho (; uppercase Ρ, lowercase ρ or ; or ) is the seventeenth letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician alphabet, Phoenician letter resh . Its uppercase form uses the same ...
GEF
Vav1 Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene. Function The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...
, are activated upon phosphorylation in response to upstream signals. Secondary messengers such as
cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...
and
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
can also play a role in GEF activation. Crosstalk has also been shown between GEFs and multiple GTPase signaling pathways. For example, SOS contains a Dbl homology domain in addition to its CDC25 catalytic domain. SOS can act as a GEF to activate
Rac1 Ras-related C3 botulinum toxin substrate 1, is a protein that in humans is encoded by the ''RAC1'' gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions. Func ...
, a RhoGTPase, in addition to its role as a GEF for Ras. SOS is therefore a link between the Ras-Family and Rho-Family GTPase signaling pathways.


Cancer

GEFs are potential target for
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
therapy due to their role in many signaling pathways, particularly cell proliferation. For example, many cancers are caused by mutations in the
MAPK/ERK pathway The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell (biology), cell that communicates a signal from a Receptor (biochemistry), receptor on the surface of the cell to the DNA in the nucleus of the cel ...
that lead to uncontrolled growth. The GEF
SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with Ras protein, Ras proteins to phosphorylate GDP into GTP, or from an inacti ...
activates Ras, whose target is the
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
Raf. Raf is a
proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
because mutations in this protein have been found in many cancers. The Rho GTPase
Vav1 Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene. Function The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...
, which can be activated by the GEF receptor, has been shown to promote tumor proliferation in pancreatic cancer. GEFs represent possible therapeutic targets as they can potentially play a role in regulating these pathways through their activation of GTPases.


Examples

*
Son of sevenless In cell signalling, ''Son of Sevenless'' (''SOS'') refers to a set of genes encoding guanine nucleotide exchange factors that act on the Ras subfamily of small GTPases. History and name The gene was so named because the Sos protein that it encod ...
(SOS1) is an important GEF in the cell growth-regulatory MAPK/ERK pathway. SOS1 binds GRB2 at the plasma membrane after EGF receptor activation. SOS1 activates the small G protein Ras. *
eIF-2 Eukaryotic Initiation Factor 2 (eIF2) is a eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer co ...
b is a eukaryotic initiation factor necessary to initiate protein translation. eIF-2b regenerates the GTP-bound form of eIF-2 for an additional cycle in protein synthesis initiation, i.e., its binding to the Met-t-RNA. *
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
are trans-membrane receptors that act as GEFs for their cognate G proteins upon binding of a ligand. Ligand binding induces a conformational change that allows the GPCR to activate an associated GTPase. *
RCC1 Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein. RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase. Interactions ...
is the guanine nucleotide exchange factor for Ran GTPase. It localizes to the nucleus and catalyzes the activation of Ran to allow nuclear export of proteins. *
Ras-GRF1 Ras-GRF1 is a guanine nucleotide exchange factor. Its function is to release guanosine diphosphate, GDP, from the signaling protein RAS, thus increasing the activity of RAS by allowing it to bind to guanosine triphosphate, GTP, returning it to i ...
*
Kalirin Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the ''KALRN'' gene. Kalir ...
*
PLEKHG2 Pleckstrin homology domain containing, family G member 2 (PLEKHG2) is a protein that in humans is encoded by the ''PLEKHG2'' gene. It is sometimes written as ARHGEF42, FLJ00018. The PLEKHG2 protein is a huge protein of about 1300 amino acids, 130 ...
* Ephexin5 is a RhoA GEF involved in neuronal synapse development.


See also

*
G proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...
*
Guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
*
Nucleotide exchange factor Nucleotide exchange factors (NEFs) are proteins that stimulate the exchange (replacement) of nucleoside diphosphates for nucleoside triphosphates bound to other proteins. Function Many cellular proteins cleave ( hydrolyze) nucleoside triphosphat ...
*
Small GTPases Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrim ...


References


External links


MBInfo - Glossary Terms: GAPs, GEFs, and GDIs
{{DEFAULTSORT:Guanine Nucleotide Exchange Factor GTP-binding protein regulators