Journal articles: 'Guanosine triphosphatase'

1

Dunn, P. P. J., A. R. Slabas, and A. L. Moore. "Characterization of cuckoo-pint (Arum maculatum) mitochondrial adenosine triphosphatases." Biochemical Journal 233, no. 3 (February 1, 1986): 839–44. http://dx.doi.org/10.1042/bj2330839.

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The catalytic properties of cuckoo-pint (Arum maculatum) mitochondrial adenosine triphosphatase have been analysed. The pH profile, effect of inhibitors, cold-stability and substrate specificity are characteristic of mitochondrial adenosine triphosphatases, although a high guanosine triphosphatase activity does appear to be restricted to plant mitochondrial adenosine triphosphatases. The kinetic properties of nucleoside 5′-triphosphate hydrolysis by membrane-bound and soluble enzymes have been studied by means of double-reciprocal plots. These plots were linear in the absence of an activating anion, which may indicate that the catalytic and/or regulatory mechanism of Arum maculatum adenosine triphosphatase is different from that of other enzyme preparations. It is suggested that the differences in subunit composition of plant and mammalian adenosine triphosphatases reported previously [Dunn, Slabas & Moore (1985) Biochem. J. 225, 821-824] are structurally, rather than functionally, significant.

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Dey, Sandip, Chiranjit Biswas, and Jayati Sengupta. "The universally conserved GTPase HflX is an RNA helicase that restores heat-damaged Escherichia coli ribosomes." Journal of Cell Biology 217, no. 7 (June 21, 2018): 2519–29. http://dx.doi.org/10.1083/jcb.201711131.

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The ribosome-associated GTPase HflX acts as an antiassociation factor upon binding to the 50S ribosomal subunit during heat stress in Escherichia coli. Although HflX is recognized as a guanosine triphosphatase, several studies have shown that the N-terminal domain 1 of HflX is capable of hydrolyzing adenosine triphosphate (ATP), but the functional role of its adenosine triphosphatase (ATPase) activity remains unknown. We demonstrate that E. coli HflX possesses ATP-dependent RNA helicase activity and is capable of unwinding large subunit ribosomal RNA. A cryo–electron microscopy structure of the 50S–HflX complex in the presence of nonhydrolyzable analogues of ATP and guanosine triphosphate hints at a mode of action for the RNA helicase and suggests the linker helical domain may have a determinant role in RNA unwinding. Heat stress results in inactivation of the ribosome, and we show that HflX can restore heat-damaged ribosomes and improve cell survival.

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Ahmadian, M. R., T. Zor, D. Vogt, W. Kabsch, Z. Selinger, A. Wittinghofer, and K. Scheffzek. "Guanosine triphosphatase stimulation of oncogenic Ras mutants." Proceedings of the National Academy of Sciences 96, no. 12 (June 8, 1999): 7065–70. http://dx.doi.org/10.1073/pnas.96.12.7065.

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Pulk, Arto, and Jamie H. D. Cate. "Control of Ribosomal Subunit Rotation by Elongation Factor G." Science 340, no. 6140 (June 27, 2013): 1235970. http://dx.doi.org/10.1126/science.1235970.

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Protein synthesis by the ribosome requires the translocation of transfer RNAs and messenger RNA by one codon after each peptide bond is formed, a reaction that requires ribosomal subunit rotation and is catalyzed by the guanosine triphosphatase (GTPase) elongation factor G (EF-G). We determined 3 angstrom resolution x-ray crystal structures of EF-G complexed with a nonhydrolyzable guanosine 5′-triphosphate (GTP) analog and bound to the Escherichia coli ribosome in different states of ribosomal subunit rotation. The structures reveal that EF-G binding to the ribosome stabilizes switch regions in the GTPase active site, resulting in a compact EF-G conformation that favors an intermediate state of ribosomal subunit rotation. These structures suggest that EF-G controls the translocation reaction by cycles of conformational rigidity and relaxation before and after GTP hydrolysis.

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Joseph, Hazel L., and Gregg Gundersen. "CDC42 guanosine triphosphatase mediates fibroblast migration after wounding." Journal of the American College of Surgeons 191, no. 4 (October 2000): S79—S80. http://dx.doi.org/10.1016/s1072-7515(00)00620-7.

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Iversen, Lars, Hsiung-Lin Tu, Wan-Chen Lin, Sune M. Christensen, Steven M. Abel, Jeff Iwig, Hung-Jen Wu, et al. "Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics." Science 345, no. 6192 (July 3, 2014): 50–54. http://dx.doi.org/10.1126/science.1250373.

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Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras–guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average.

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Sprink, Thiemo, David J. F. Ramrath, Hiroshi Yamamoto, Kaori Yamamoto, Justus Loerke, Jochen Ismer, Peter W. Hildebrand, et al. "Structures of ribosome-bound initiation factor 2 reveal the mechanism of subunit association." Science Advances 2, no. 3 (March 2016): e1501502. http://dx.doi.org/10.1126/sciadv.1501502.

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Throughout the four phases of protein biosynthesis—initiation, elongation, termination, and recycling—the ribosome is controlled and regulated by at least one specified translational guanosine triphosphatase (trGTPase). Although the structural basis for trGTPase interaction with the ribosome has been solved for the last three steps of translation, the high-resolution structure for the key initiation trGTPase, initiation factor 2 (IF2), complexed with the ribosome, remains elusive. We determine the structure of IF2 complexed with a nonhydrolyzable guanosine triphosphate analog and initiator fMet-tRNAiMet in the context of the Escherichia coli ribosome to 3.7-Å resolution using cryo-electron microscopy. The structural analysis reveals previously unseen intrinsic conformational modes of the 70S initiation complex, establishing the mutual interplay of IF2 and initator transfer RNA (tRNA) with the ribsosome and providing the structural foundation for a mechanistic understanding of the final steps of translation initiation.

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Danilenko, Mikhail P., Vera C. Turmukhambetova, Oleg V. Yesirev, Vsevolod A. Tkachuk, and Mikhail P. Panchenko. "Na+-K+-ATPase-G protein coupling in myocardial sarcolemma: separation and reconstitution." American Journal of Physiology-Lung Cellular and Molecular Physiology 261, no. 4 (October 1, 1991): L87—L91. http://dx.doi.org/10.1152/ajplung.1991.261.4.l87.

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The cholinergic agonist carbachol produces a concentration-dependent (half-maximum inhibitory concentration = 0.9 μM) decrease in the Na+-K+-adenosine triphosphatase (ATPase) activity of rabbit cardiac sarcolemma that occurred only in the presence of guanosine 5'-[ggr-thio]triphosphate (0.1 μM GTPggrS) and reached 40% inhibition. The inhibition is blocked by the muscarinic receptor antagonist atropine (10 μM) and is abolished in sarcolemma treated with pertussis toxin (20 μg/ml) in the presence of 100 μM NAD. GTPggrS alone reduces Na+-K+-ATPase activity by 45% (half-maximum inhibitory = 1 μM). The apparent affinity of the enzyme for GTPgγS is increased ≈10-fold in the presence of 1 μM carbachol. In sarcolemma solubilized with the zwitterionic detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS, 10 mM), the GTPgγS-dependent inhibition of the Na+-K+-ATPase is also observed. Gel filtration of a CHAPS extract of sarcolemma on a Sepharose CL-6B column resulted in a separation of Na+-K+-ATPase and pertussis toxin-sensitive Gi activities. Na+-K+-ATPase activity that was separated on the column lost its sensitivity to the inhibitory action of guanine nucleotides. Inhibitory effects (20–30%) of guanosine 5'-triphosphate analogues [Gpp(NH)p, GTPggrS, or Gpp(CH2)p] at micromolar concentrations were restored when the Na+-K+-ATPase activity was recombined with fractions that contained the pertussis toxin-sensitive Gi protein(s). Similar concentrations of guanosine 5'-triphosphate, guanosine 5'-diphosphate, guanosine-5' -[beta-thio]diphosphate, or App(NH)p were unable to induce the Gi protein-mediated attenuation of Na+-K+-ATPase activity in the reconstitution system. These results suggest that a pertussis toxin-sensitive Gi protein may act as a transducer of the inhibitory hormonal signals on Na+-K+-ATPase in the sarcolemma. cardiac sarcolemma

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Danilenko, Mikhail P., Vera C. Turmukhambetova, Oleg V. Yesirev, Vsevolod A. Tkachuk, and Mikhail P. Panchenko. "Na+-K+-ATPase-G protein coupling in myocardial sarcolemma: separation and reconstitution." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 4 (October 1, 1991): 87–91. http://dx.doi.org/10.1152/ajpheart.1991.261.4.87.

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The cholinergic agonist carbachol produces a concentration-dependent (half-maximum inhibitory concentration = 0.9 μM) decrease in the Na+-K+-adenosine triphosphatase (ATPase) activity of rabbit cardiac sarcolemma that occurred only in the presence of guanosine 5'-[-thio]triphosphate (0.1 μM GTPS) and reached 40% inhibition. The inhibition is blocked by the muscarinic receptor antagonist atropine (10 μM) and is abolished in sarcolemma treated with pertussis toxin (20 μg/ml) in the presence of 100 μM NAD. GTPS alone reduces Na+–K+-ATPaseactivity by 45% (half-maximum inhibitory = 1 μM). The apparent affinity of the enzyme for GTPS is increased 10-fold in the presence of 1 μM carbachol. In sarcolemma solubilized with the zwitterionic detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS, 10 mM), the GTPS-dependent inhibition of the Na+-K+-ATPase is also observed. Gel filtration of a CHAPS extract of sarcolemma on a Sepharose CL–6B column resulted in a separation of Na+-K+-ATPase and pertussis toxin-sensitive Gi activities. Na+-K+-ATPase activity that was separated on the column lost its sensitivity to the inhibitory action of guanine nucleotides. Inhibitory effects (20–30%) of guanosine 5'-triphosphate analogues [Gpp(NH)p, GTPS, or Gpp(CH2)p] at micromolar concentrations were restored when the Na+-K+-ATPase activity was recombined with fractions that contained the pertussis toxin-sensitive Gi protein(s). Similar concentrations of guanosine 5'-triphosphate, guanosine 5'-diphosphate, guanosine-5'-[β-thio]diphosphate, or App(NH)p were unable to induce the Gi protein-mediated attenuation of Na+-K+-ATPase activity in the reconstitution system. These results suggest that a pertussis toxin-sensitive Gi protein may act as a transducer of the inhibitory hormonal signals on Na+-K+-ATPase in the sarcolemma. cardiac sarcolemma

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10

Cambot, Marie, Sandra Aresta, Brigitte Kahn-Perlès, Jean de Gunzburg, and Paul-Henri Roméo. "Human Immune Associated Nucleotide 1: a member of a new guanosine triphosphatase family expressed in resting T and B cells." Blood 99, no. 9 (May 1, 2002): 3293–301. http://dx.doi.org/10.1182/blood.v99.9.3293.

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Abstract TAL-1 is a basic helix-loop-helix oncoprotein that is expressed in up to 30% of T-cell acute lymphoblastic leukemias but not in the T lineage. We have cloned a complementary DNA, called Human Immune Associated Nucleotide 1 (hIAN1), whose messenger RNA (mRNA) level expression is inversely correlated to the TAL-1 mRNA level in human leukemic T-cell lines. The hIAN1 encodes a 38-kd protein that belongs to a novel family of proteins conserved from plants to humans and characterized by motifs related to, but highly divergent from, the consensus motifs found in guanosine triphosphate (GTP)–binding proteins. Despite these divergent amino acids at positions involved in GTP/guanosine diphosphate (GDP) binding and guanosine triphosphatase (GTPase) activities, we found that hIAN1 specifically binds GDP (Kd = 0.47 μM) and GTP (Kd = 6 μM) and exhibits intrinsic GTPase activity. Among mature hematopoietic cells, hIAN1 is specifically expressed in resting T and B lymphocytes, and its expression level tremendously decreased at the protein but not the mRNA level during B- or T-lymphocyte activation, suggesting a specific role for this new type of GTPase during the immune response.

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Walker, David M., Ruifei Wang, and Lauren J. Webb. "Conserved electrostatic fields at the Ras–effector interface measured through vibrational Stark effect spectroscopy explain the difference in tilt angle in the Ras binding domains of Raf and RalGDS." Phys. Chem. Chem. Phys. 16, no. 37 (2014): 20047–60. http://dx.doi.org/10.1039/c4cp00743c.

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Vibrational Stark effect (VSE) spectroscopy was used to measure the electrostatic fields present at the interface of the human guanosine triphosphatase (GTPase) Ras docked with the Ras binding domain (RBD) of the protein kinase Raf.

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Yang, Mei, Chen Liang, Kunchithapadam Swaminathan, Stephanie Herrlinger, Fan Lai, Ramin Shiekhattar, and Jian-Fu Chen. "A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy." Science Advances 2, no. 9 (September 2016): e1601167. http://dx.doi.org/10.1126/sciadv.1601167.

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The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.

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Takizawa, Toshihiro, and Takuma Saito. "Guanosine triphosphatase activity demonstrated by freeze substitution enzyme histochemistry." Proceedings, annual meeting, Electron Microscopy Society of America 48, no. 3 (August 12, 1990): 886–87. http://dx.doi.org/10.1017/s0424820100161990.

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During the past three decades, the freeze substitution fixation technique has been developed to observe fine morphology in close to the living state. Recently, this freeze substitution fixation has been successfully applied to enzyme histochemistry demonstrating the active sites of enzymes as well as their active state at the time of quenching. in this study, we have undertaken to study guanosine triphosphatase (GTPase), one of the key enzymes in the cGMP cascade, on the rod outer segment after freeze substitution fixation and have compared the results with those obtained from conventional immersion fixation enzyme histochemistry at the ultrastructural level.Freeze substitution fixation: After Nembutal anesthesia, frog, Xenopus laevis, eyes were excised and the neural retinae were gently separated from the pigment epithelium. The retinae were then rapid frozen using a quick freezing device, the E7200 Slammer (Polaron, Equipment Ltd. England), contacting on an ultrapure copper block at -196°C of liquid nitrogen.

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Shan, Shu-ou, Sowmya Chandrasekar, and Peter Walter. "Conformational changes in the GTPase modules of the signal reception particle and its receptor drive initiation of protein translocation." Journal of Cell Biology 178, no. 4 (August 6, 2007): 611–20. http://dx.doi.org/10.1083/jcb.200702018.

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During cotranslational protein targeting, two guanosine triphosphatase (GTPase) in the signal recognition particle (SRP) and its receptor (SR) form a unique complex in which hydrolyses of both guanosine triphosphates (GTP) are activated in a shared active site. It was thought that GTP hydrolysis drives the recycling of SRP and SR, but is not crucial for protein targeting. Here, we examined the translocation efficiency of mutant GTPases that block the interaction between SRP and SR at specific stages. Surprisingly, mutants that allow SRP–SR complex assembly but block GTPase activation severely compromise protein translocation. These mutations map to the highly conserved insertion box domain loops that rearrange upon complex formation to form multiple catalytic interactions with the two GTPs. Thus, although GTP hydrolysis is not required, the molecular rearrangements that lead to GTPase activation are essential for protein targeting. Most importantly, our results show that an elaborate rearrangement within the SRP–SR GTPase complex is required to drive the unloading and initiate translocation of cargo proteins.

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Saito, Kota, Koh Yamashiro, Noriko Shimazu, Tomoya Tanabe, Kenji Kontani, and Toshiaki Katada. "Concentration of Sec12 at ER exit sites via interaction with cTAGE5 is required for collagen export." Journal of Cell Biology 206, no. 6 (September 8, 2014): 751–62. http://dx.doi.org/10.1083/jcb.201312062.

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Mechanisms for exporting variably sized cargo from the endoplasmic reticulum (ER) using the same machinery remain poorly understood. COPII-coated vesicles, which transport secretory proteins from the ER to the Golgi apparatus, are typically 60–90 nm in diameter. However, collagen, which forms a trimeric structure that is too large to be accommodated by conventional transport vesicles, is also known to be secreted via a COPII-dependent process. In this paper, we show that Sec12, a guanine-nucleotide exchange factor for Sar1 guanosine triphosphatase, is concentrated at ER exit sites and that this concentration of Sec12 is specifically required for the secretion of collagen VII but not other proteins. Furthermore, Sec12 recruitment to ER exit sites is organized by its direct interaction with cTAGE5, a previously characterized collagen cargo receptor component, which functions together with TANGO1 at ER exit sites. These findings suggest that the export of large cargo requires high levels of guanosine triphosphate–bound Sar1 generated by Sec12 localized at ER exit sites.

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Merlini, Laura, Bita Khalili, Omaya Dudin, Laetitia Michon, Vincent Vincenzetti, and Sophie G. Martin. "Inhibition of Ras activity coordinates cell fusion with cell–cell contact during yeast mating." Journal of Cell Biology 217, no. 4 (February 16, 2018): 1467–83. http://dx.doi.org/10.1083/jcb.201708195.

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In the fission yeast Schizosaccharomyces pombe, pheromone signaling engages a signaling pathway composed of a G protein–coupled receptor, Ras, and a mitogen-activated protein kinase (MAPK) cascade that triggers sexual differentiation and gamete fusion. Cell–cell fusion requires local cell wall digestion, which relies on an initially dynamic actin fusion focus that becomes stabilized upon local enrichment of the signaling cascade on the structure. We constructed a live-reporter of active Ras1 (Ras1–guanosine triphosphate [GTP]) that shows Ras activity at polarity sites peaking on the fusion structure before fusion. Remarkably, constitutive Ras1 activation promoted fusion focus stabilization and fusion attempts irrespective of cell pairing, leading to cell lysis. Ras1 activity was restricted by the guanosine triphosphatase–activating protein Gap1, which was itself recruited to sites of Ras1-GTP and was essential to block untimely fusion attempts. We propose that negative feedback control of Ras activity restrains the MAPK signal and couples fusion with cell–cell engagement.

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Li, Wen, Zheng Liu, Ravi Kiran Koripella, Robert Langlois, Suparna Sanyal, and Joachim Frank. "Activation of GTP hydrolysis in mRNA-tRNA translocation by elongation factor G." Science Advances 1, no. 4 (May 2015): e1500169. http://dx.doi.org/10.1126/sciadv.1500169.

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During protein synthesis, elongation of the polypeptide chain by each amino acid is followed by a translocation step in which mRNA and transfer RNA (tRNA) are advanced by one codon. This crucial step is catalyzed by elongation factor G (EF-G), a guanosine triphosphatase (GTPase), and accompanied by a rotation between the two ribosomal subunits. A mutant of EF-G, H91A, renders the factor impaired in guanosine triphosphate (GTP) hydrolysis and thereby stabilizes it on the ribosome. We use cryogenic electron microscopy (cryo-EM) at near-atomic resolution to investigate two complexes formed by EF-G H91A in its GTP state with the ribosome, distinguished by the presence or absence of the intersubunit rotation. Comparison of these two structures argues in favor of a direct role of the conserved histidine in the switch II loop of EF-G in GTPase activation, and explains why GTP hydrolysis cannot proceed with EF-G bound to the unrotated form of the ribosome.

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Soubias, Olivier, Shashank Pant, Frank Heinrich, Yue Zhang, Neeladri Sekhar Roy, Jess Li, Xiaoying Jian, et al. "Membrane surface recognition by the ASAP1 PH domain and consequences for interactions with the small GTPase Arf1." Science Advances 6, no. 40 (September 2020): eabd1882. http://dx.doi.org/10.1126/sciadv.abd1882.

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Adenosine diphosphate–ribosylation factor (Arf) guanosine triphosphatase–activating proteins (GAPs) are enzymes that need to bind to membranes to catalyze the hydrolysis of guanosine triphosphate (GTP) bound to the small GTP-binding protein Arf. Binding of the pleckstrin homology (PH) domain of the ArfGAP With SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) to membranes containing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is key for maximum GTP hydrolysis but not fully understood. By combining nuclear magnetic resonance, neutron reflectometry, and molecular dynamics simulation, we show that binding of multiple PI(4,5)P2 molecules to the ASAP1 PH domain (i) triggers a functionally relevant allosteric conformational switch and (ii) maintains the PH domain in a well-defined orientation, allowing critical contacts with an Arf1 mimic to occur. Our model provides a framework to understand how binding of the ASAP1 PH domain to PI(4,5)P2 at the membrane may play a role in the regulation of ASAP1.

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Liu, Yuan, Kunio Nakatsukasa, Michiko Kotera, Akira Kanada, Takashi Nishimura, Tsutomu Kishi, Satoru Mimura, and Takumi Kamura. "Non–SCF-type F-box protein Roy1/Ymr258c interacts with a Rab5-like GTPase Ypt52 and inhibits Ypt52 function." Molecular Biology of the Cell 22, no. 9 (May 2011): 1575–84. http://dx.doi.org/10.1091/mbc.e10-08-0716.

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Skp1/Cul1/F-box (SCF)–type F-box proteins are a component of the Cullin-RING SCF ubiquitin E3 ligase, which is involved in numerous cellular processes. However, the function of non–SCF-type F-box proteins remains largely unknown. The Rab5-like small guanosine 5′-triphosphatase Vps21/Ypt51 is a key regulator of intracellular transportation; however, deletion of its isoforms, Ypt52 and Ypt53, results in only a modest inhibition of intracellular trafficking. The function of these proteins therefore remains largely elusive. Here we analyze the role of a previously uncharacterized non–SCF-type F-box protein, Roy1/Ymr258c, in cell growth and intracellular transport in Saccharomyces cerevisiae. Roy1 binds to Ypt52 under physiological conditions, and Skp1 is indispensable for the association of Roy1 with Ypt52. The vps21Δ yeast cells exhibit severe deficiencies in cell growth and intracellular trafficking, whereas simultaneous deletion of roy1 alleviates the defects caused by deletion of vps21. However, additional disruption of ypt52 in roy1Δvps21Δ cells largely suppresses the cell growth and trafficking observed in roy1Δvps21Δ cells. We demonstrate that Roy1 interacts with guanosine 5′-diphosphate–bound and nucleotide-free Ypt52 and thereby inhibits the formation of guanosine 5′-triphosphate–bound, active Ypt52. These results thus indicate that Roy1 negatively modulates cell viability and intracellular transport by suppressing Ypt52.

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Treuner-Lange, Anke, Eric Macia, Mathilde Guzzo, Edina Hot, Laura M. Faure, Beata Jakobczak, Leon Espinosa, et al. "The small G-protein MglA connects to the MreB actin cytoskeleton at bacterial focal adhesions." Journal of Cell Biology 210, no. 2 (July 13, 2015): 243–56. http://dx.doi.org/10.1083/jcb.201412047.

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In Myxococcus xanthus the gliding motility machinery is assembled at the leading cell pole to form focal adhesions, translocated rearward to propel the cell, and disassembled at the lagging pole. We show that MglA, a Ras-like small G-protein, is an integral part of this machinery. In this function, MglA stimulates the assembly of the motility complex by directly connecting it to the MreB actin cytoskeleton. Because the nucleotide state of MglA is regulated spatially and MglA only binds MreB in the guanosine triphosphate–bound form, the motility complexes are assembled at the leading pole and dispersed at the lagging pole where the guanosine triphosphatase activating protein MglB disrupts the MglA–MreB interaction. Thus, MglA acts as a nucleotide-dependent molecular switch to regulate the motility machinery spatially. The function of MreB in motility is independent of its function in peptidoglycan synthesis, representing a coopted function. Our findings highlight a new function for the MreB cytoskeleton and suggest that G-protein–cytoskeleton interactions are a universally conserved feature.

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Jeon, Taeck J., Dai-Jen Lee, Susan Lee, Gerald Weeks, and Richard A. Firtel. "Regulation of Rap1 activity by RapGAP1 controls cell adhesion at the front of chemotaxing cells." Journal of Cell Biology 179, no. 5 (November 26, 2007): 833–43. http://dx.doi.org/10.1083/jcb.200705068.

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Spatial and temporal regulation of Rap1 is required for proper myosin assembly and cell adhesion during cell migration in Dictyostelium discoideum. Here, we identify a Rap1 guanosine triphosphatase–activating protein (GAP; RapGAP1) that helps mediate cell adhesion by negatively regulating Rap1 at the leading edge. Defects in spatial regulation of the cell attachment at the leading edge in rapGAP1− (null) cells or cells overexpressing RapGAP1 (RapGAP1OE) lead to defective chemotaxis. rapGAP1− cells have extended chemoattractant-mediated Rap1 activation kinetics and decreased MyoII assembly, whereas RapGAP1OE cells show reciprocal phenotypes. We see that RapGAP1 translocates to the cell cortex in response to chemoattractant stimulation and localizes to the leading edge of chemotaxing cells via an F-actin–dependent pathway. RapGAP1 localization is negatively regulated by Ctx, an F-actin bundling protein that functions during cytokinesis. Loss of Ctx leads to constitutive and uniform RapGAP1 cortical localization. We suggest that RapGAP1 functions in the spatial and temporal regulation of attachment sites through MyoII assembly via regulation of Rap1–guanosine triphosphate.

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Morin-Leisk, Jeanne, Simran G. Saini, Xin Meng, Alexander M. Makhov, Peijun Zhang, and Tina H. Lee. "An intramolecular salt bridge drives the soluble domain of GTP-bound atlastin into the postfusion conformation." Journal of Cell Biology 195, no. 4 (November 7, 2011): 605–15. http://dx.doi.org/10.1083/jcb.201105006.

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Endoplasmic reticulum (ER) network branching requires homotypic tethering and fusion of tubules mediated by the atlastin (ATL) guanosine triphosphatase (GTPase). Recent structural studies on the ATL soluble domain reveal two dimeric conformers proposed to correspond to a tethered prefusion state and a postfusion state. How the prefusion conformer transitions to the postfusion conformer is unknown. In this paper, we identify an intramolecular salt bridge mediated by two residues outside the GTPase domain near the point of rotation that converts the prefusion dimer to the postfusion state. Charge reversal of either residue blocked ER network branching, whereas a compensatory charge reversal to reestablish electrostatic attraction restored function. In vitro assays using the soluble domain revealed that the salt bridge was dispensable for GTP binding and hydrolysis but was required for forming the postfusion dimer. Unexpectedly, the postfusion conformation of the soluble domain was achieved when bound to the nonhydrolyzable GTP analogue guanosine 5′-[β,γ-imido]triphosphate, suggesting that nucleotide hydrolysis might not be required for the prefusion to postfusion conformational change.

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Hasegawa, Keisuke, Sung Jin Ryu, and Petr Kaláb. "Chromosomal gain promotes formation of a steep RanGTP gradient that drives mitosis in aneuploid cells." Journal of Cell Biology 200, no. 2 (January 14, 2013): 151–61. http://dx.doi.org/10.1083/jcb.201206142.

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Many mitotic factors were shown to be activated by Ran guanosine triphosphatase. Previous studies in Xenopus laevis egg extracts and in highly proliferative cells showed that mitotic chromosomes were surrounded by steep Ran guanosine triphosphate (GTP) concentration gradients, indicating that RanGTP-activated factors promote spindle assembly around chromosomes. However, the mitotic role of Ran in normal differentiated cells is not known. In this paper, we show that although the steep mitotic RanGTP gradients were present in rapidly growing cell lines and were required for chromosome congression in mitotic HeLa cells, the gradients were strongly reduced in slow-growing primary cells, such as HFF-1 fibroblasts. The overexpression of RCC1, the guanine nucleotide exchange factor for Ran, induced steeper mitotic RanGTP gradients in HFF-1 cells, showing the critical role of RCC1 levels in the regulation of mitosis by Ran. Remarkably, in vitro fusion of HFF-1 cells produced cells with steep mitotic RanGTP gradients comparable to HeLa cells, indicating that chromosomal gain can promote mitosis in aneuploid cancer cells via Ran.

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Richardson, Kenneth E., Paul Tannous, Kambeez Berenji, Bridgid Nolan, Kayla J. Bayless, George E. Davis, Beverly A. Rothermel, and Joseph A. Hill. "Guanosine Triphosphatase Activation Occurs Downstream of Calcineurin in Cardiac Hypertrophy*." Journal of Investigative Medicine 53, no. 8 (December 2005): 414–24. http://dx.doi.org/10.2310/6650.2005.53805.

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Kanaho, Y., P. P. Chang, J. Moss, and M. Vaughan. "Mechanism of inhibition of transducin guanosine triphosphatase activity by vanadate." Journal of Biological Chemistry 263, no. 33 (November 1988): 17584–89. http://dx.doi.org/10.1016/s0021-9258(19)77875-2.

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Swart, Guido W. M., and Andrea Parmeggiani. "TRNA and the guanosine triphosphatase activity of elongation factor Tu." Biochemistry 28, no. 1 (January 10, 1989): 327–32. http://dx.doi.org/10.1021/bi00427a044.

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Dos Vultos, T., J. Blázquez, J. Rauzier, I. Matic, and B. Gicquel. "Identification of Nudix Hydrolase Family Members with an Antimutator Role in Mycobacterium tuberculosis and Mycobacterium smegmatis." Journal of Bacteriology 188, no. 8 (April 15, 2006): 3159–61. http://dx.doi.org/10.1128/jb.188.8.3159-3161.2006.

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ABSTRACT Mycobacterium tuberculosis and Mycobacterium smegmatis MutT1, MutT2, MutT3, and Rv3908 (MutT4) enzymes were screened for an antimutator role. Results indicate that both MutT1, in M. tuberculosis and M. smegmatis, and MutT4, in M. smegmatis, have that role. Furthermore, an 8-oxo-guanosine triphosphatase function for MutT1 and MutT2 is suggested.

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SHI, Yu-long, Rui-zheng MIAO, Li CHENG, Xiao-bo GUO, Bo YANG, Chang-qing JING, Li ZHANG, Xing JIN, and Le-ping LI. "Up-regulation of T-lymphoma and metastasis gene 1 in gastric cancer and its involvement in cell invasion and migration." Chinese Medical Journal 126, no. 4 (February 20, 2013): 640–45. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20122167.

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Background T-lymphoma and metastasis gene 1 (Tiam1) produces a guanine nucleotide exchange factor (GNEF) that regulates guanosine triphosphatase, which transforms guanosine diphosphate to guanosine triphosphate. Recently published data indicate that Tiam1 was associated with gastric cancer. The aim of this study was to investigate biological effects and potential mechanisms of Tiam1 in gastric carcinoma. Methods We analyzed the expression of Tiam1 in 114 pair-matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time PCR. We investigated Tiam1 expression and its prognostic value for gastric cancer. Furthermore, the functions of Tiam1 over-expression were analyzed with stable-expression Tiam1 plasmid in human gastric cancer cell lines. Results Tiam1 expression was significantly associated with cell differentiation and lymphatic metastasis; expression of Tiam1 mRNA was up-regulated in gastric cancer compared to pair-matched adjacent non-tumor tissues. Analyses of surgical tissue samples and 5-year survival of gastric cancer patients showed that those with strong Tiam1 expression had significantly shorter overall survival time than those with negative Tiam1 expression. Ectopic expression of Tiam1 promoted cell growth, migration and invasion of gastric cancer cells in vitro. Conclusions In gastric cancer cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may be a marker of gastric cancer progression and metastasis in a subset of cancer.

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Genot, Elisabeth. "ARF1 at the crossroads of podosome construction and function." Journal of Cell Biology 216, no. 1 (December 22, 2016): 13–15. http://dx.doi.org/10.1083/jcb.201611097.

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Podosomes are actin-based proteolytic microdomains of the plasma membrane found in cells that travel across tissues. In this issue, Rafiq et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201605104) reveal that the small guanosine triphosphatase ARF1, a well-known orchestrator of membrane traffic at the Golgi, regulates podosome formation, maintenance, and function.

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Jacobson, J. R., S. M. Dudek, P. Singelton, and J. G. N. Garcia. "29 ENDOTHELIAL CELL BARRIER ENHANCEMENT BY ADENOSINE TRIPHOSPHATE IS MEDIATED BY THE SMALL GUANOSINE TRIPHOSPHATASE RAC." Journal of Investigative Medicine 53, no. 2 (March 1, 2005): S361.5—S361. http://dx.doi.org/10.2310/6650.2005.00206.28.

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Nakagawa, Takefumi, Hideo Hirakata, Masami Sato, Kumi Nakamura, Yoshio Hatano, Takashi Nakamura, and Kazuhiko Fukuda. "Ketamine Suppresses Platelet Aggregation Possibly by Suppressed Inositol Triphosphate Formation and Subsequent Suppression of Cytosolic Calcium Increase." Anesthesiology 96, no. 5 (May 1, 2002): 1147–52. http://dx.doi.org/10.1097/00000542-200205000-00018.

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Background Ketamine has been shown to suppress platelet aggregation, but its mechanisms of action have not been defined. The purpose of the current study is to clarify the effects of ketamine on human platelet aggregation and to elucidate the underlying mechanisms of its action. Methods Platelet aggregation was measured using an eight-channel aggregometer, and cytosolic free calcium concentration was measured in Fura-2/AM-loaded platelets using a fluorometer. Inositol 1,4,5-triphosphate (IP3) was measured with use of a commercially available IP3 assay kit. To estimate thromboxane A2 (TXA2) receptor binding affinity and expression, Scatchard analysis was performed using [3H]S145, a specific TXA2 receptor antagonist. TXA2 agonist binding assay was also performed. The membrane-bound guanosine 5'-triphosphatase activity was determined using [gamma-32P]guanosine triphosphate by liquid scintillation analyzer. Results Ketamine (500 microm) suppressed aggregation induced by adenosine diphosphate (0.5 microm), epinephrine (1 microm), (+)-9,11-epithia-11,12-methano-TXA2 (STA2) (0.5 microm), and thrombin (0.02 U/ml) to 39.1 +/- 30.9, 46.3 +/- 4.3, -2.0 +/- 16.8, and 86.6 +/- 1.4% of zero-control, respectively. Ketamine (250 microm-1 mm) also suppressed thrombin- and STA2-induced cytosolic free calcium concentration increase dose dependently. Although ketamine (2 mm) had no effect on TXA2 receptor expression and its binding affinity, it (1 mm) suppressed intracellular peak IP3 concentrations induced by thrombin and STA2 from 6.60 +/- 1.82 and 4.39 +/- 2.41 to 2.41 +/- 0.98 and 1.90 +/- 0.86 pmol/109 platelets, respectively, and it suppressed guanosine triphosphate hydrolysis induced by thrombin (0.02 units/ml) and STA2 (0.5 microm) to 50.3 +/- 3.2 and 67.5 +/- 5.5% versus zero-control, respectively. Conclusion Ketamine inhibits human platelet aggregation possibly by suppressed IP3 formation and subsequent suppression of cytosolic free calcium concentration. The site of action of ketamine is neither TXA2 nor thrombin binding sites but possibly receptor-coupled mechanisms, including G-protein.

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Rojas, Raul, Thijs van Vlijmen, Gonzalo A. Mardones, Yogikala Prabhu, Adriana L. Rojas, Shabaz Mohammed, Albert J. R. Heck, Graça Raposo, Peter van der Sluijs, and Juan S. Bonifacino. "Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7." Journal of Cell Biology 183, no. 3 (November 3, 2008): 513–26. http://dx.doi.org/10.1083/jcb.200804048.

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The retromer complex mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network (TGN). Mammalian retromer is composed of a sorting nexin (SNX) dimer that binds to phosphatidylinositol 3-phosphate–enriched endosomal membranes and a vacuolar protein sorting (Vps) 26/29/35 trimer that participates in cargo recognition. The mammalian SNX dimer is necessary but not sufficient for recruitment of the Vps26/29/35 trimer to membranes. In this study, we demonstrate that the guanosine triphosphatase Rab7 contributes to this recruitment. The Vps26/29/35 trimer specifically binds to Rab7–guanosine triphosphate (GTP) and localizes to Rab7-containing endosomal domains. Interference with Rab7 function causes dissociation of the Vps26/29/35 trimer but not the SNX dimer from membranes. This blocks retrieval of mannose 6-phosphate receptors to the TGN and impairs cathepsin D sorting. Rab5-GTP does not bind to the Vps26/29/35 trimer, but perturbation of Rab5 function causes dissociation of both the SNX and Vps26/29/35 components from membranes through inhibition of a pathway involving phosphatidylinositol 3-kinase. These findings demonstrate that Rab5 and Rab7 act in concert to regulate retromer recruitment to endosomes.

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Miller, J. L., C. M. Hubbard, B. J. Litman, and T. L. Macdonald. "Inhibition of transducin activation and guanosine triphosphatase activity by aluminum ion." Journal of Biological Chemistry 264, no. 1 (January 1989): 243–50. http://dx.doi.org/10.1016/s0021-9258(17)31250-4.

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Zhang, Jiaming, Daniel R. Hill, and Anne W. Sylvester. "Diversification of the RAB Guanosine Triphosphatase Family in Dicots and Monocots." Journal of Integrative Plant Biology 49, no. 8 (August 2007): 1129–41. http://dx.doi.org/10.1111/j.1672-9072.2007.00520.x.

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Otomo, Masahiro, Kiyofumi Takahashi, Hiroshi Miyoshi, Kenichi Osada, Hideki Nakashima, and Noboru Yamaguchi. "Some Selective Serotonin Reuptake Inhibitors Inhibit Dynamin I Guanosine Triphosphatase (GTPase)." Biological & Pharmaceutical Bulletin 31, no. 8 (2008): 1489–95. http://dx.doi.org/10.1248/bpb.31.1489.

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Jacobson, J. R., W. Chen, and J. G. N. Garcia. "Role of Rac Guanosine Triphosphatase in Simvastatin-Mediated Endothelial Cell Signaling." Journal of Investigative Medicine 54, no. 2_suppl (March 2006): 354. http://dx.doi.org/10.1177/108155890605402s63.

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Yu, Wenjie, Hao Jiang, Fengjiao Liu, Ze Li, Lingxia Xu, Chang Liu, Wenfa Lv, et al. "KRAS Affects the Lipid Composition by Regulating Mitochondrial Functions and MAPK Activation in Bovine Mammary Epithelial Cells." Animals 12, no. 22 (November 8, 2022): 3070. http://dx.doi.org/10.3390/ani12223070.

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Kirsten rat sarcoma viral oncogene homolog (KRAS), or guanosine triphosphatase KRAS, is a proto-oncogene that encodes the small guanosine triphosphatase transductor protein. Previous studies have found that KRAS can promote cytokine secretion, cell chemotaxis, and survival. However, its effects on milk fat synthesis in bovine mammary epithelial cells are unclear. In this study, the effects of KRAS inhibition on cell metabolism, autophagy, oxidative stress, endoplasmic reticulum stress, mitochondrial function, and lipid composition as well as the potential mechanisms were detected in an immortalized dairy cow mammary epithelial cell line (MAC-T). The results showed that inhibition of KRAS changed the lipid composition (especially the triglyceride level), mitochondrial functions, autophagy, and endoplasmic reticulum stress in cells. Moreover, KRAS inhibition regulated the levels of the mammalian target of rapamycin and mitogen-activated protein kinase (extracellular regulated protein kinases, c-Jun N-terminal kinases, p38) activation. These results indicated that regulation of KRAS would affect the synthesis and composition of milk fat. These results are also helpful for exploring the synthesis and secretion of milk fat at the molecular level and provide a theoretical basis for improving the percentage of fat in milk and the yield of milk from cows.

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Hollmann, Markus W., Susanne Herroeder, Katrin S. Kurz, Christian W. Hoenemann, Danja Struemper, Klaus Hahnenkamp, and Marcel E. Durieux. "Time-dependent Inhibition of G Protein–coupled Receptor Signaling by Local Anesthetics." Anesthesiology 100, no. 4 (April 1, 2004): 852–60. http://dx.doi.org/10.1097/00000542-200404000-00015.

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Background Several beneficial effects of local anesthetics (LAs) were shown to be due to inhibition of G protein-coupled receptor signaling. Differences in exposure time might explain discrepancies in concentrations of LAs required to achieve these protective effects in vivo and in vitro (approximately 100-fold higher). Using Xenopus oocytes and human neutrophils, the authors studied time-dependent effects of LAs on G protein-coupled receptor signaling and characterized possible mechanisms and sites of action. Methods Measurement of agonist-induced Ca2+-activated Cl currents, using a two-electrode voltage clamp technique, and determination of superoxide anion production by cytochrome c assay were used to assess the effects of LAs on G protein-coupled receptor signaling in oocytes and primed and activated human neutrophils, respectively. Antisense knockdown of G alpha q protein and inhibition of various proteins within the signaling pathway served for defining mechanisms and sites of action more specifically. Results LAs attenuated G protein-coupled receptor signaling in both models in a time-dependent and reversible manner (lidocaine reduced lysophosphatidic acid signaling to 19 +/- 3% after 48 h and 25 +/- 2% after 6 h of control response in oocytes and human neutrophils, respectively). Whereas no effect was observed after extracellularly applied or intracellularly injected QX314, a lidocaine analog, using G alpha q-depleted oocytes, time-dependent inhibition also occurred after intracellular injection of QX314 into undepleted oocytes. Inhibition of phosphatases or protein kinases and agonist-independent G-protein stimulation, using guanosine 5'-O-3-thiotriphosphate or aluminum fluoride, did not affect time-dependent inhibition by LAs. Conclusion Inhibition of G protein-coupled receptor signaling by LAs was found to be time dependent and reversible. Critically requiring G alpha q-protein function, this effect is located downstream of guanosine diphosphate-guanosine triphosphate exchange and is not dependent on increased guanosine triphosphatase activity, phosphatases, or protein kinases.

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Bandekar, Sumit J., Nadia Arang, Ena S. Tully, Brittany A. Tang, Brenna L. Barton, Sheng Li, J. Silvio Gutkind, and John J. G. Tesmer. "Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential." Science Signaling 12, no. 569 (February 19, 2019): eaav2449. http://dx.doi.org/10.1126/scisignal.aav2449.

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The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/11-coupled G protein–coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gαq/11binding. Here, we determined the crystal structure of TrioC in its basal state and found that the pleckstrin homology (PH) domain interacts with the Dbl homology (DH) domain in a manner that occludes the Rho GTPase binding site, thereby suggesting the molecular basis of TrioC autoinhibition. Biochemical and biophysical assays revealed that disruption of the autoinhibited conformation destabilized and activated the TrioC module in vitro. Last, mutations in the DH-PH interface found in patients with cancer activated TrioC and, in the context of full-length Trio, led to increased abundance of guanosine triphosphate–bound RhoA (RhoA·GTP) in human cells. These mutations increase mitogenic signaling through the RhoA axis and, therefore, may represent cancer drivers operating in a Gαq/11-independent manner.

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Lyons, Leah S., Shuyun Rao, Wayne Balkan, Joanne Faysal, Carol A. Maiorino, and Kerry L. Burnstein. "Ligand-Independent Activation of Androgen Receptors by Rho GTPase Signaling in Prostate Cancer." Molecular Endocrinology 22, no. 3 (March 1, 2008): 597–608. http://dx.doi.org/10.1210/me.2007-0158.

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Abstract Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.

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Jacobson, J. R., W. Chen, and J. G. N. Garcia. "63 ROLE OF RAC GUANOSINE TRIPHOSPHATASE IN SIMVASTATIN-MEDIATED ENDOTHELIAL CELL SIGNALING." Journal of Investigative Medicine 54, no. 2 (March 1, 2006): S354.1—S354. http://dx.doi.org/10.2310/6650.2005.x0015.62.

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Lupashin, V. V. "t-SNARE Activation Through Transient Interaction with a Rab-Like Guanosine Triphosphatase." Science 276, no. 5316 (May 23, 1997): 1255–58. http://dx.doi.org/10.1126/science.276.5316.1255.

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Nekrasova, Elina R., David M. Berman, Richard R. Rustandi, Heidi E. Hamm, Alfred G. Gilman, and Vadim Y. Arshavsky. "Activation of Transducin Guanosine Triphosphatase by Two Proteins of the RGS Family†." Biochemistry 36, no. 25 (June 1997): 7638–43. http://dx.doi.org/10.1021/bi970427r.

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Li, B. "Role of the Guanosine Triphosphatase Rac2 in T Helper 1 Cell Differentiation." Science 288, no. 5474 (June 23, 2000): 2219–22. http://dx.doi.org/10.1126/science.288.5474.2219.

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Schulze, Ryan J., Karuna Rasineni, Shaun G. Weller, Micah B. Schott, Barbara Schroeder, Carol A. Casey, and Mark A. McNiven. "Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7." Hepatology Communications 1, no. 2 (March 10, 2017): 140–52. http://dx.doi.org/10.1002/hep4.1021.

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Blader, Ira J., M. Jamie T. V. Cope, Trevor R. Jackson, Adam A. Profit, Angela F. Greenwood, David G. Drubin, Glenn D. Prestwich, and Anne B. Theibert. "GCS1, an Arf Guanosine Triphosphatase-activating Protein in Saccharomyces cerevisiae, Is Required for Normal Actin Cytoskeletal Organization In Vivo and Stimulates Actin Polymerization In Vitro." Molecular Biology of the Cell 10, no. 3 (March 1999): 581–96. http://dx.doi.org/10.1091/mbc.10.3.581.

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Recent cloning of a rat brain phosphatidylinositol 3,4,5-trisphosphate binding protein, centaurin α, identified a novel gene family based on homology to an amino-terminal zinc-binding domain. In Saccharomyces cerevisiae, the protein with the highest homology to centaurin α is Gcs1p, the product of theGCS1 gene. GCS1 was originally identified as a gene conditionally required for the reentry of cells into the cell cycle after stationary phase growth. Gcs1p was previously characterized as a guanosine triphosphatase-activating protein for the small guanosine triphosphatase Arf1, and gcs1 mutants displayed vesicle-trafficking defects. Here, we have shown that similar to centaurin α, recombinant Gcs1p bound phosphoinositide-based affinity resins with high affinity and specificity. A novelGCS1 disruption strain (gcs1Δ) exhibited morphological defects, as well as mislocalization of cortical actin patches. gcs1Δ was hypersensitive to the actin monomer-sequestering drug, latrunculin-B. Synthetic lethality was observed between null alleles of GCS1 andSLA2, the gene encoding a protein involved in stabilization of the actin cytoskeleton. In addition, synthetic growth defects were observed between null alleles of GCS1 andSAC6, the gene encoding the yeast fimbrin homologue. Recombinant Gcs1p bound to actin filaments, stimulated actin polymerization, and inhibited actin depolymerization in vitro. These data provide in vivo and in vitro evidence that Gcs1p interacts directly with the actin cytoskeleton in S. cerevisiae.

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Shah, Ankur H., Nicholas L. Cianciola, Jeffrey L. Mills, Frank D. Sönnichsen, and Cathleen Carlin. "Adenovirus RIDα regulates endosome maturation by mimicking GTP-Rab7." Journal of Cell Biology 179, no. 5 (November 26, 2007): 965–80. http://dx.doi.org/10.1083/jcb.200702187.

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The small guanosine triphosphatase Rab7 regulates late endocytic trafficking. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein–related protein 1L (ORP1L) are guanosine triphosphate (GTP)–Rab7 effectors that instigate minus end–directed microtubule transport. We demonstrate that RILP and ORP1L both interact with the group C adenovirus protein known as receptor internalization and degradation α (RIDα), which was previously shown to clear the cell surface of several membrane proteins, including the epidermal growth factor receptor and Fas (Carlin, C.R., A.E. Tollefson, H.A. Brady, B.L. Hoffman, and W.S. Wold. 1989. Cell. 57:135–144; Shisler, J., C. Yang, B. Walter, C.F. Ware, and L.R. Gooding. 1997. J. Virol. 71:8299–8306). RIDα localizes to endocytic vesicles but is not homologous to Rab7 and is not catalytically active. We show that RIDα compensates for reduced Rab7 or dominant-negative (DN) Rab7(T22N) expression. In vitro, Cu2+ binding to RIDα residues His75 and His76 facilitates the RILP interaction. Site-directed mutagenesis of these His residues results in the loss of RIDα–RILP interaction and RIDα activity in cells. Additionally, expression of the RILP DN C-terminal region hinders RIDα activity during an acute adenovirus infection. We conclude that RIDα coordinates recruitment of these GTP-Rab7 effectors to compartments that would ordinarily be perceived as early endosomes, thereby promoting the degradation of selected cargo.

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Gagnon, Matthieu G., Jinzhong Lin, David Bulkley, and Thomas A. Steitz. "Crystal structure of elongation factor 4 bound to a clockwise ratcheted ribosome." Science 345, no. 6197 (August 7, 2014): 684–87. http://dx.doi.org/10.1126/science.1253525.

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Elongation factor 4 (EF4/LepA) is a highly conserved guanosine triphosphatase translation factor. It was shown to promote back-translocation of tRNAs on posttranslocational ribosome complexes and to compete with elongation factor G for interaction with pretranslocational ribosomes, inhibiting the elongation phase of protein synthesis. Here, we report a crystal structure of EF4–guanosine diphosphate bound to the Thermus thermophilus ribosome with a P-site tRNA at 2.9 angstroms resolution. The C-terminal domain of EF4 reaches into the peptidyl transferase center and interacts with the acceptor stem of the peptidyl-tRNA in the P site. The ribosome is in an unusual state of ratcheting with the 30S subunit rotated clockwise relative to the 50S subunit, resulting in a remodeled decoding center. The structure is consistent with EF4 functioning either as a back-translocase or a ribosome sequester.

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McMurray, M. M., J. S. Hansen, B. E. Haley, D. J. Takemoto, and L. J. Takemoto. "Interspecies conservation of retinal guanosine 5′-triphosphatase. Characterization by photoaffinity labelling and tryptic-peptide mapping." Biochemical Journal 225, no. 1 (January 1, 1985): 227–32. http://dx.doi.org/10.1042/bj2250227.

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Light-activated hydrolysis of cyclic GMP is achieved through the photoexcitation of rhodopsin, a process which then triggers the replacement of GDP for GTP by a retinal guanosine 5′-triphosphatase referred to as ‘transducin’. The transducin-GTP complex then switches on the phosphodiesterase [Fung, Hurley & Stryer (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 152-156]. The bovine transducin consists of an alpha-subunit (39000 Mr), which is a GTP-binding component, together with a beta-(37000 Mr) and a gamma-subunit (10000 Mr). We have purified retinal transducin from cow, pig, chick and frog. The enzyme specific activities and sodium dodecyl sulphate/polyacrylamide-gel-electrophoretic profiles indicate that this enzyme is similar in all species except the frog. Whereas the bovine, pig and chick transducins consist of major 37000- and 39000-Mr components, that of the frog consists of a single 75000-Mr component. Labelling of the GTP-binding components with the photoaffinity label 8-azidoguanosine [gamma-32P]triphosphate demonstrated that the 37000-Mr components of the cow, pig and chick and the 75000-Mr component of the frog were major GTP-binding components. In addition, peptide maps of radioiodinated tryptic peptides indicate that the frog 75000-Mr protein is highly related to the pig transducin. These results demonstrate evolutionary conservation of retinal transducin and the presence of a higher-Mr, but nonetheless highly conserved form, of transducin in the frog. The relationship of this component to the recently reported rod-outer-segment inhibitor protein [Yamazaki, Stein, Chernoff & Bitensky (1983) J. Biol. Chem. 258, 8188-8194] is discussed.

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Wakabayashi, Junko, Zhongyan Zhang, Nobunao Wakabayashi, Yasushi Tamura, Masahiro Fukaya, Thomas W. Kensler, Miho Iijima, and Hiromi Sesaki. "The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice." Journal of Cell Biology 186, no. 6 (September 14, 2009): 805–16. http://dx.doi.org/10.1083/jcb.200903065.

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The dynamin-related guanosine triphosphatase Drp1 mediates the division of mitochondria and peroxisomes. To understand the in vivo function of Drp1, complete and tissue-specific mouse knockouts of Drp1 were generated. Drp1-null mice die by embryonic day 11.5. This embryonic lethality is not likely caused by gross energy deprivation, as Drp1-null cells showed normal intracellular adenosine triphosphate levels. In support of the role of Drp1 in organelle division, mitochondria formed extensive networks, and peroxisomes were elongated in Drp1-null embryonic fibroblasts. Brain-specific Drp1 ablation caused developmental defects of the cerebellum in which Purkinje cells contained few giant mitochondria instead of the many short tubular mitochondria observed in control cells. In addition, Drp1-null embryos failed to undergo developmentally regulated apoptosis during neural tube formation in vivo. However, Drp1-null embryonic fibroblasts have normal responses to apoptotic stimuli in vitro, suggesting that the apoptotic function of Drp1 depends on physiological cues. These findings clearly demonstrate the physiological importance of Drp1-mediated organelle division in mice.

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Journal articles on the topic 'Guanosine triphosphatase'

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