Small GTP-binding proteins. Physiol Rev
ABSTRACT Small GTP-binding proteins (G proteins) exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than 100 members. This superfamily is structurally classified into at least five families: the Ras, Rho, Rab, Sar1/Arf, and Ran families. They regulate a wide variety of cell functions as biological timers (biotimers) that initiate and terminate specific cell functions and determine the periods of time for the continuation of the specific cell functions. They furthermore play key roles in not only temporal but also spatial determination of specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. Many upstream regulators and downstream effectors of small G proteins have been isolated, and their modes of activation and action have gradually been elucidated. Cascades and cross-talks of small G proteins have also been clarified. In this review, functions of small G proteins and their modes of activation and action are described.
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- "The reciprocal NMR studies of effector binding to RAS and its oncogenic mutants, where RAS is isotopically enriched, established a hierarchy of effector binding to HRAS in which BRAF RBD displayed the highest-affinity binding, and provide an elegant approach for directly monitoring the complex RAS signaling network (Smith and Ikura, 2014; Smith et al., 2013). The RAS subfamily of guanine nucleotide-binding proteins (G proteins), comprising three major isoforms in humans (HRAS, KRAS, and NRAS), are small monomeric GTPases that play a critical role in numerous signal transduction pathways associated with cell growth and differentiation, and many human cancers (Stephen et al., 2014; Takai et al., 2001). RAS proteins function as molecular switches, oscillating between inactive GDP-bound and active GTP-bound states; the latter can bind and activate a variety of effector proteins and signaling pathways . "
ABSTRACT: RAS binding is a critical step in the activation of BRAF protein serine/threonine kinase and stimulation of the mitogen-activated protein kinase signaling pathway. Mutations in both RAS and BRAF are associated with many human cancers. Here, we report the solution nuclear magnetic resonance (NMR) and X-ray crystal structures of the RAS-binding domain (RBD) from human BRAF. We further studied the complex between BRAF RBD and the GppNHp bound form of HRAS in solution. Backbone, side-chain, and (19)F NMR chemical shift perturbations reveal unexpected changes distal to the RAS-binding face that extend through the core of the RBD structure. Moreover, backbone amide hydrogen/deuterium exchange NMR data demonstrate conformational ensemble changes in the RBD core structure upon complex formation. These changes in BRAF RBD reveal a basis for allosteric regulation of BRAF structure and function, and suggest a mechanism by which RAS binding can signal the drastic domain rearrangements required for activation of BRAF kinase. Copyright © 2015 Elsevier Ltd. All rights reserved.Structure 07/2015; DOI:10.1016/j.str.2015.06.003 · 6.79 Impact Factor
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- "Small GTP-binding proteins (GTPase) are monomeric G proteins which function as molecular switches to regulate biological processes . These proteins are grouped into five subfamilies: Ras, Rho (Ras homologue), Arf/Sar, Ran and Rab/Ypt (Takai et al., 2001). Among these groups, proteins of the RAS and RHO families are the best characterized in fungi. "
ABSTRACT: Small GTPases of the Rho family play an important role in regulating biological processes in fungi. In this study, we mainly investigated the biological functions of Rho3 in Botrytis cinerea, and found that deletion of the rho3 from B. cinerea significantly suppressed vegetative growth and conidiation, reduced appressorium formation and decreased virulence. Microscopy analysis revealed that the distance between septa was increased in the Δrho3 mutant. In addition, mitochondria were suggested to be the main sources of intracellular reactive oxygen species (ROS) in B. cinerea based on dual staining with 2’, 7’-dichlorodihydrofluorescein diacetate and MitoTracker orange. The Δrho3 mutant showed less accumulation of ROS in the hyphae tips compared to the WT strain of B. cinerea. These results provide the novel evidence to ascertain the function of small GTPase Rho3 in regulating growth, conidiation and virulence of B. cinerea.Fungal Genetics and Biology 01/2015; 75. DOI:10.1016/j.fgb.2015.01.007 · 3.26 Impact Factor
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- "It is challenging to explain how these very similar effector-binding domains coordinate the different functions of Ras and Rap proteins, which are presumably mediated by different effector molecules. The ability of these small GTPases to signal requires that the GTP-bound state engage specific downstream effectors, interactions that are geographically limited to the cytosolic surface of cellular membranes (Takai et al., 2001). GTPases are targeted to membranes as a result of the post-translational modification process. "
ABSTRACT: Ras and Rap proteins are closely related small guanosine triphosphatase (GTPases) that share similar effector-binding domains but operate in a very different signaling networks; Ras has a dominant role in cell proliferation, while Rap mediates cell adhesion. Ras and Rap proteins are regulated by several shared processes such as post-translational modification, phosphorylation, activation by guanine exchange factors and inhibition by GTPase-activating proteins. Sub-cellular localization and trafficking of these proteins to and from the plasma membrane are additional important regulatory features that impact small GTPases function. Despite its importance, the trafficking mechanisms of Ras and Rap proteins are not completely understood. Chaperone proteins play a critical role in trafficking of GTPases and will be the focus of the discussion in this work. We will review several aspects of chaperone biology focusing on specificity toward particular members of the small GTPase family. Understanding this specificity should provide key insights into drug development targeting individual small GTPases.Critical Reviews in Biochemistry and Molecular Biology 12/2014; DOI:10.3109/10409238.2014.989308 · 5.81 Impact Factor