GTPase activating proteins: structural and functional insights 18 years after discovery

Scheffzek, Klaus; Ahmadian, Mohammad Réza

doi:10.1007/s00018-005-5136-x

Cited by 132 publications

(107 citation statements)

References 319 publications

(444 reference statements)

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“…GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). The GTP binding and hydrolysis take place in the highly conserved G domain common to all GTPases (Scheffzek and Ahmadian, 2005). The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms ranging from yeast to mammals.…”

Section: Prostate Cancer Mirnasmentioning

confidence: 99%

Expression profile analysis reveals putative prostate cancer-related microRNAs

Song

Liu²,

Pan³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Annotation of prostate cancer (PC) genomes provides a foundation for discoveries that can improve the understanding and treatment of the disease. Therefore, in the present study, we used the Student t-test to identify differentially expressed PC-related mRNAs and microRNAs (miRNAs). Then, we performed interrelated mapping of miRNA target genes between abnormally expressed mRNAs and miRNAs, and explored mRNA-target miRNA interrelated pairs to explain the biological functions of miRNA during the progression of PC, thus revealing the occurrence of miRNA-mediated PC. After Gene Set Functional Similarity analysis, we obtained 20 abnormal PC-related candidate miRNAs, including hsa-miR-26a, hsa-miR-152, hsa-miR19a, hsa-miR-30c, hsa-miR-19b, and hsa-miR-146b-5p, among others. These results suggest that it may be possible to predict the clinical behavior of prostate cancer based on gene expression analysis.

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Section: Prostate Cancer Mirnasmentioning

confidence: 99%

Expression profile analysis reveals putative prostate cancer-related microRNAs

Song

Liu²,

Pan³

et al. 2013

Genet. Mol. Res.

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“…Despite great progress in structural and biochemical studies of G-proteins and related systems (for reviews, see Coleman & Sprang, 1999 ;Geyer et al 1997 ;Scheffzek & Ahmadian, 2005 ;Sprang, 1997b ;Vetter & Wittinghofer, 1999 ;Wittinghofer, 2006), we still do not have a complete understanding of the detailed molecular mechanism of these proteins. For example, the reasons for the oncogenic effect of some Ras mutations are not clear.…”

Section: Introductionmentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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“…Similar to other smgs, Rac's activity depends on GTP binding, and declines slowly due to the slow GTPhydrolytic activity of the protein. GTPase activating proteins (GAPs) accelerate GTPhydrolysis by several orders of magnitude, and thus serve as important temporal regulators of smg-signaling [29,30]. The human genome contains approx 70 potential Rho-family GAPs [31,32] from which each cell type expresses its own "GAP-repertoire" [33].…”

Section: Introductionmentioning

confidence: 99%

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Lörincz

Szarvas

Smith

et al. 2014

Free Radical Biology and Medicine

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Precise spatiotemporal regulation of O2 •--generating NADPH oxidases (Nox) is a vital requirement. In the case of Nox1-3, which depend on the small GTPase Rac, acceleration of GTP hydrolysis by GTPase activating protein (GAP) could represent a feasible temporal control mechanism. Our goal was to investigate the molecular interactions between RacGAPs and phagocytic Nox2 in neutrophilic granulocytes. In structural studies we revealed that simultaneous interaction of Rac with its effector protein p67 phox and regulatory protein RacGAP was sterically possible. The effect of RacGAPs was experimentally investigated in a cell-free O2 •--generating system consisting of isolated membranes and recombinant p47 phox and p67 phox proteins. Addition of soluble RacGAPs decreased O2 •--production and there was no difference in the effect of four RacGAPs previously identified in neutrophils. Depletion of membrane-associated RacGAPs had selective effect: a decrease in ARHGAP1 or ARHGAP25 level increased O2 •--production but a depletion of ARHGAP35 had no effect.Only membrane-localized RacGAPs seem to be able to interact with Rac when it is assembled in the Nox2 complex. Thus, in neutrophils multiple RacGAPs are involved in the control of O2 •--production by Nox2, allowing selective regulation via different signaling pathways.

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GTPase activating proteins: structural and functional insights 18 years after discovery

Cited by 132 publications

References 319 publications

Expression profile analysis reveals putative prostate cancer-related microRNAs

Expression profile analysis reveals putative prostate cancer-related microRNAs

Why nature really chose phosphate

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

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