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GTP Binding Proteins (Low Molecular Weight)

The approximately 150 members of the human Ras superfamily of low molecular weight GTP binding proteins function as regulators of diverse cellular processes. Most Ras superfamily members have intrinsic GTP hydrolyzing activity, which allows them to cycle between inactive GDP-bound and active GTP-bound states. In their active conformation, Ras family members can interact with a variety of effector proteins. By changing the localization of effectors, by altering their interaction with other proteins, or by modifying their enzymatic activity, Ras superfamily members mediate their diverse downstream functions.

GDP/GTP cycling of Ras superfamily members is controlled by Guanine nucleotide Exchange Factors (GEFs), which activate GTPases by promoting GTP for GDP exchange, and by GTPase Activating Proteins (GAPs), which stimulate their intrinsic GTPase activity, thus causing their inactivation. Some GTPases are also controlled by a third class of regulator, termed Guanine nucleotide Dissociation Inhibitors (GDIs), which can extract GTPases from membranes and maintain them in their inactive state in the cytosol. Only few GDIs have been characterized, but close to 160 human genes are predicted to encode GAPs and a similar number of GEFs may exist. An ever increasing number of proteins (currently at least 350) have been implicated as potential effectors based on their ability to interact with Ras superfamily members. Thus, over 3% of human genes may encode Ras superfamily members, their regulators or potential effectors.

The Ras superfamily is named after first human oncogene, discovered as the cellular homolog of a rat sarcoma virus transforming sequence 25 years ago. While the role of GTPase defective Ras mutants in cancer is well understood, the medical relevance of this gene family extends well beyond Ras itself. Thus, several diseases and developmental disorders have been attributed to defects in GTPases (see accompanying table), GAPs (e.g. neurofibromatosis-1, tuberous sclerosis), GEFs (e.g. amyotrophic lateral sclerosis, Aarskog syndrome), or effector proteins (e.g. Wiskott-Aldrich syndrome, nonsyndromic X-linked mental retardation).

Members of the Ras superfamily are found in all eukaryotes and their functions are evolutionary conserved. Based on structural and functional similarities, the Ras superfamily is usually divided into the Arf, Rab, Ran, Ras, and Rho branches. The human genome predicts over 30 Arf related proteins, more than 65 Rab family members, a single Ran GTPase, about 35 Ras paralogs, and 20 Rho family members. Among major processes involving these proteins, Arf and Rab GTPases control vesicular trafficking, Ran controls the directionality of nucleocytoplasmic transport and directs mitotic spindle assembly, while Ras and Rho GTPases function in signal transduction.

Some proteins within each Ras superfamily branch have been extensively studied, while others received little attention. Among Arfs, Arf1 controls Golgi vesicle budding at least in part through its interaction with Golgi-associated adaptor protein complexes. Arf6 is located at the plasma membrane and controls actin remodeling and endocytic vesicle trafficking. Rab GTPases determine the specificity of endocytic and exocytic vesicular transport and form the largest branch of the Ras superfamily. Critical to the function of Ran in nucleocytoplasmic transport is a Ran-GDP/GTP gradient across the nuclear membrane. This gradient reflects the opposite actions of a chromatin-associated RanGEF and a cytoplasmic RanGAP. The Ras branch includes the highly related K-Ras, K-Ras, and N-Ras isoforms, which are activated in response to a variety of extracellular signals. Active Ras in turn activates cytoplasmic signaling proteins, including Raf and PI-3 kinases. Crosstalk between GTPases is a common theme. For example, Ras interacts with RalGEFs, and multiple links have been identified between Ras and Rho GTPases. Among the latter group, RhoA, Rac1 and Cdc42 have several functions, but are best known for their roles in directing specific F-actin rearrangements.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

  Arf

Rab Ran
Structural Information Arf1
181 aa (human)
Rab1A
205 aa (human)
Ran
216 aa (human)
Mammalian Members Arf 1-6
Arl 1-13
Sar1a,b
Other paralogs
Rab 1-43 plus
Other paralogs
Ran
Post-translational Modification Myristoylation
N-terminal acetylation
Geranylgeranylation None
Inhibitory Bacterial Toxins Not Known Not Known Not Known
Activating Bacterial Toxins Not Known Not Known Not Known
Major Physiological Function Control of Golgi vesicle budding
Actin remodeling
Vesicular trafficking Bidirectional nucleocytoplasmic transport
Mitotic spindle assembly
Disease Relevance Bardet-Biedl syndrome (Arl6)
Lipid absorption disorders (Sar1b)
Griscelli syndrome (Rab27A) Not Known

 

 

  Ras

Rho
Structural Information H-Ras
186 aa (human)
RhoA
193 aa (human)
Mammalian Members Ras (H-, K-, -N)
R-Ras (1, 2, 3)
Ral (A, B)
Rap1 (a, b)
Rap2 (a, b, c)
Other paralogs
Rho (A, B, C)
Rac (1, 2, 3)
Cdc42
RhoD
RhoE, Rnd2, Rnd3
Other paralogs
Post-translational Modification Farnesylation
Geranylgeranylation
Palmitoylation
Farnesylation
Geranylgeranylation
Inhibitory Bacterial Toxins Clostridium species toxins
(e.g. C. sordelli lethal toxin or C. difficile toxin B-1470)
Clostridium species toxins (e.g. C. difficile toxin B-10463 (C4102))
C. botulinum exoenzyme C3 (A8724)
Activating Bacterial Toxins Not Known Escherichia coli cytotoxic necrotizing factor (CNF) 1 and 2
Bordetella pertussis dermonecrotic toxin (DNT)
Major Physiological Function Signal transduction Signal transduction
Actin remodeling
Disease Relevance Cancer (K-, H-, N-Ras, ARHI) Myeloid dysfunction (Rac2)

 

Abbreviations

Arf: ADP ribosylation factor
Rab: Ras genes from rat brain
Ran: Ras-related nuclear
Rap: Ras related protein
Ras: Rat sarcoma
Rho: Ras homolog

 

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References