Introduction to monomeric G protein Small GTPases, also widely

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Last updated: November 11, 2019

Introduction to monomeric G protein Small GTPases, also widely known as monomeric guanine nucleotide binding proteins, are part of a group of hydrolase enzymes of size ranging 21 to 30 kDa that belongs to the Rho family of GTPases. They are part of a family of small signalling G proteins and is a subfamily of the Ras superfamily. The originating members of this superfamily are the Ras oncogene proteins which can be further divided into five branches based on their differences in sequence and their functional abilities, and they are Ras, Rho, Ran, Rab, and Arf. Numerous members of the Rho family have displayed their ability to regulate and mediate different cell functions and survival, and controls various aspects of intracellular actin dynamics.

They are mostly found in all eukaryotic families including plants and yeast. In the mid-1980s Rho family of GTPases was first discovered, while RhoA was then later identified in 1985 through an isolation from a cDNA screening. Following, Rac1 and Rac2 were discovered in the late 1980s and lastly Cdc42 in the year 1990. Until the late 1990s, eight other mammalian Rho members were discovered from different biological screenings and lead to the availability of complete genome sequences on the full identification of gene families. In mammals, the Rho family contain up to 22 members and all eukaryotes essentially contain Rho GTPases unless otherwise stated. These members are then re-divided into different subfamily for example, the Rac subfamily that include Rac1, Rac2, the Cdc42 subfamily which consist of Cdc42, TC10, and TCL, the RhoA subfamily that include RhoA, RhoB, and RhoC and other Rho GTPases such as RhoE/Rnd3, and RhoD. Each Rho proteins controls specific downstream effectors and exert different signals to induce specific cell processes (Etienne-Manneville and Hall, 2002).

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Similarly, Ras proteins are also involved in cell signalling, and cooperate with specific downstream proteins which may affect the regulation of cytoplasmic signalling networks and result in the regulation of gene expression and cell proliferation (figure 1). Members of the Rho family had exhibited their involvement in cell polarity, regulation of cytoskeletal organization and also been shown to be involved in haematopoiesis.. Particularly, the RAC protein has been shown to be involved in both the canonical and noncanonical Wnt signalling pathway.The formation of stress fibers and focal adhesions in mammalian fibroblasts is activated by RhoA, whereas the formation of microspikes is induced by Cdc42. Guanine nucleotide exchange factor, also known as GEFs are proteins that are responsible for the activation of GTPases through the releasing of GDP so that GTP would be allowed to bind. Two unrelated families of Guanine Exchange Factors activate Rho GTPases and carry either a Dbl-homology (DH) domain or a Dock Homology Region (DHR) domain. A GEF activity of the enzyme phospholipase D2 towards Rac2 has also been seen, though further studies are needed.

Vesicular trafficking and the trafficking of proteins between different organelles via different ways such as the endocytotic and secretory pathways are primarily mediated by the Rab family. These proteins aid with the budding from the donor compartment, the passage to acceptors, vesicle fusion, and lastly cargo release. Specific intracellular distribution of its different members is a key feature of the Rab Family. It is the largest family of the Ras superfamily known to us due to the gene duplication that is observed in all vertebrate genomes. Rab GTPases are activated by at least four types of RabGEFs and it is the RabGEFs subfamilies that carry a Vps9 domain or a DENN domain which is expressed differently and the TRAPP complex in yeast, the Sec2A. Apart from the Rab family, one member of the Ran family is found in typically all eukaryotic lineages, apart from plants, which contain several copies. The most abundant proteins in eukaryotic cells are RAN proteins.

They are important factors that mediate nuclear import and export via the nuclear pore complex and are crucial factors involved in the development of mitotic spindle and the formation of the nuclear envelope. Lastly, the Arf family of proteins consist of the most divergent proteins and function similarly to the Rab family proteins in terms of vesicle trafficking. These proteins have a common trait as they have a much larger GDP/GTP conformational change as compared to other subfamilies.

Signalling of these proteins involves a wide range of effectors such as the coat complexes (COP and AP1) and lipid-modifying enzymes (PLD1) Typically, all small GTPases consist of conserved domains that are made up of 5 alpha helices that surround a 6-stranded beta-sheet. In the primary level, five highly conserved ‘G motifs’ G1-G5, holds invariant residues that take charge over important interaction with different nucleotides and as well as essential Mg2+ ion (P-loop with Gx4GKS/T signature) that essentially requires high affinity nucleotide binding and the hydrolytic activity of GTP (figure 2). The Ras superfamily consist of five subfamilies grouped in accord to their sequence homologies that matches their own functional parts in the cell.

Each individual subfamily has their own associated GEFs and GAPs, each with specific nucleotide exchange factor and GTPase activating and lipid binding domains. For some of the subfamilies, they too have specific GDIs. GEFs (Guanine nucleotide exchange factors) are protein domains that are responsible for the activation of GTPases by stimulating the dissociation of guanosine diphosphate(GDP) thus allow the binding of guanosine triphosphate(GTP) in its place.

Some GEFs can activate multiple GTPases while others are specific to a single GTPase.The binding of GTP to the GTPase result in the release of GEF, which can also activate a new GTPase. Thus, GEFs is able to stabilize the nucleotide-free GTPases before another GTP binds to it, and also able to destabilize the GTPase interaction with GDP. GAPs (GTPase-activating protein) are proteins that inactivate GTPases through the hydrolysis of GTP, thereby allowing the transfer of the GTPase back inactive state at the last step of stimulation cycle (figure 3).In addition to the GDP/GTP exchange, most Rho/Rac proteins require the binding onto the cell membrane to exert their biological functions. This anchoring step is dependent of a combination of intrinsic signals and the cooperative signalling events that takes place, and is different from other Ras proteins. In intrinsic tethering signals, the most important step is the post-translational modification of the GTPase ”CAAX box”. It is the addition of either a geranyl-geranyl or a farnesyl group into the cysteine residue of the CAAX box.

These enzymes are similar proteins and they specifically recognize the CAAX box at the C-terminus of the targeted protein. Once the isoprenoid group is being attached to the CAAX box, it further enhanced the translocation of small GTPases to the surface of endoplasmic reticulum where proteolytic cleavage takes place, via the isoprenyl with Rce1, a CAAX specific protease. Lastly, the exposed ?-carboxyl group of C terminal cysteine residue is being methyl esterified by carboxyl methyltransferase Icmt. The function of the newly modified GTPases largely depend on how other intrinsic signals are being processed thus determining various effects such as cell proliferation, survival and gene expression.

 Small GTPases as targets for bacteria exotoxins 7 Bacteria are capable in secreting exotoxins that may cause various types of damage to host cells such as the disruption of normal cellular metabolism and may cause serious side effect to the human host which involves nausea, diarrhoea, and serious complications. Exotoxins may be either secreted or released during the lysis of the cell  Pathogens, typically gram-negative, are able to form outer membrane vesicles consisting of lipopolysaccharide endotoxin together with virulence proteins and various toxins located in the vesicles resulting in crucial damage to membrane vesicle trafficking. It plays an important part as it largely involves the movement of various biochemical signalling molecules, and are mostly active at the host pathogen interface.

Bacteria pathogens have come a long way since their ancestors, and have formed various smart strategies to interact with mammalian cells. Other than the cross-talk between host cells and the bacteria, they also largely serve as primary virulence factors and interact with the eukaryotic machinery, favouring their own survival by either producing toxins favourable to them or by initiating the widespread of bacteria. Toxins can act in different ways, and certain toxins directly target the surface of host cells that cause alterations to the normal transduction of cell signalling. Some other toxins may transfer the active domain into the cytoplasm via endocytosis or by direct delivery and thereby modifying cytosolic targets.

Such changes in the host cells may lead to the impairment or disruption of certain metabolic pathways such as the Rho GTPases, which plays an important role in the regulation of intracellular actin dynamics (figure 4).  Some widely known exotoxins, for example, are botulinum toxin produced by Clostridium botulinum in diphtheria and the exotoxin tetanospasmin produced by Clostridium tetani. Toxic properties of mostly all exotoxins can be either heat treated or chemically treated in order to produce a toxoid. A toxoid, whose toxicity has been inactivated, can be widely used as an antitoxin and they are used as a vaccine to prevent diseases such as diphtheria, tetanus, and botulism. Majority of exotoxins are categorized into specific subgroups, and are divided according to their secretion system used to release the toxin, by toxic effectors of type VI secretion system, toxins that target tissues such as neurotoxins affecting the nervous system, and by the domain architecture of the toxin which is also known as polymorphic toxins.

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