Invited review: Small GTPases and their GAPs

Mishra, Ashwini K.; Lambright, David G.

doi:10.1002/bip.22833

Cited by 64 publications

(78 citation statements)

References 199 publications

(337 reference statements)

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“…GTP hydrolysis is providing its usual thermodynamic role of driving coupled equilibria in the cell, in this family often for cellular work in cargo transport. 155 …”

Section: Intersection and Convergence Of The Posttranslational Momentioning

confidence: 99%

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Walsh

Tang³

2017

Chem. Rev.

227

203

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Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron paths, leaving it kinetically stable to the vast majority of organic cellular metabolites.

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“…GTP hydrolysis is providing its usual thermodynamic role of driving coupled equilibria in the cell, in this family often for cellular work in cargo transport. 155 …”

Section: Intersection and Convergence Of The Posttranslational Momentioning

confidence: 99%

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Walsh

Tang³

2017

Chem. Rev.

227

203

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“…The small GTP binding proteins are a family of cytoplasmic GDP/GTP-binding proteins with GTPase activity (Rho, Ras, Rac, Raf), that serve as biomolecular switches inside the cell to regulate a variety of cellular processes [265]. The activation/deactivation cycle of these small GTP-binding proteins is tightly regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors which catalyze the exchange of GDP by GTP and thereby activate these small regulatory proteins.…”

Section: Toxins and Their Target Of Actionmentioning

confidence: 99%

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

Lahiani

Yavin

Lazarovici

2017

Toxins

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An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal’s signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A2 (PLA2) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.

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“…1B and 2A). Both proteins contain a P-loop GTPase domain, termed the G-domain, which contains the GI–GIV sequence motifs conserved in most GTPases[14, 15]. In both proteins, an N-terminal four helix bundle termed the N-domain packs against the G-domain to form a structural and functional unit called the NG domain (Fig.…”

Section: The Srp/sr Heterodimer: Gtpase Tangos Drive Co-translationalmentioning

confidence: 99%

ATPase and GTPase Tangos Drive Intracellular Protein Transport

Shan

2016

Trends in Biochemical Sciences

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The GTPase superfamily of proteins provides molecular switches to regulate numerous cellular processes. The ‘GTPase switch’ paradigm, in which external regulatory factors control the switch of a GTPase between ‘on’ and ‘off’ states, has been used to interpret the regulatory mechanism of many GTPases. However, recent work unveiled a class of nucleotide hydrolases that do not adhere to this classical paradigm. Instead, they use nucleotide-dependent dimerization cycles to regulate key cellular processes. Here, we summarize recent studies of dimeric GTPases and ATPases involved in intracellular protein targeting. We suggest that these proteins can use the conformational plasticity at their dimer interface to generate multiple points of regulation, thereby providing the driving force and spatiotemporal coordination of complex cellular pathways.

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Invited review: Small GTPases and their GAPs

Cited by 64 publications

References 199 publications

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

ATPase and GTPase Tangos Drive Intracellular Protein Transport

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