scholarly journals PseudoGTPase domains in p190RhoGAP proteins: a mini-review

2018 ◽  
Vol 46 (6) ◽  
pp. 1713-1720 ◽  
Author(s):  
Amy L. Stiegler ◽  
Titus J. Boggon
Keyword(s):  
Family Members ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Signaling Proteins ◽  
New Family ◽  
Gtpase Activating Proteins ◽  
Rho Family ◽  
Biochemical Analyses ◽  
Catalytic Cleft

Pseudoenzymes generally lack detectable catalytic activity despite adopting the overall protein fold of their catalytically competent counterparts, indeed ‘pseudo’ family members seem to be incorporated in all enzyme classes. The small GTPase enzymes are important signaling proteins, and recent studies have identified many new family members with noncanonical residues within the catalytic cleft, termed pseudoGTPases. To illustrate recent discoveries in the field, we use the p190RhoGAP proteins as an example. p190RhoGAP proteins (ARHGAP5 and ARHGAP35) are the most abundant GTPase activating proteins for the Rho family of small GTPases. These are key regulators of Rho signaling in processes such as cell migration, adhesion and cytokinesis. Structural biology has complemented and guided biochemical analyses for these proteins and has allowed discovery of two cryptic pseudoGTPase domains, and the re-classification of a third, previously identified, GTPase-fold domain as a pseudoGTPase. The three domains within p190RhoGAP proteins illustrate the diversity of this rapidly expanding pseudoGTPase group.

scholarly journals Identification and characterization of a new isoform of small GTPase RhoE

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yuan Dai ◽  
Weijia Luo ◽  
Xiaojing Yue ◽  
Wencai Ma ◽  
Jing Wang ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Biological Functions ◽  
Coding Region ◽  
Alternative Translation ◽  
Rho Family ◽  
Binding Capability ◽  
Identification And Characterization

Abstract The Rho family of GTPases consists of 20 members including RhoE. Here, we discover the existence of a short isoform of RhoE designated as RhoEα, the first Rho GTPase isoform generated from alternative translation. Translation of this new isoform is initiated from an alternative start site downstream of and in-frame with the coding region of the canonical RhoE. RhoEα exhibits a similar subcellular distribution while its protein stability is higher than RhoE. RhoEα contains binding capability to RhoE effectors ROCK1, p190RhoGAP and Syx. The distinct transcriptomes of cells with the expression of RhoE and RhoEα, respectively, are demonstrated. The data propose distinctive and overlapping biological functions of RhoEα compared to RhoE. In conclusion, this study reveals a new Rho GTPase isoform generated from alternative translation. The discovery provides a new scope of understanding the versatile functions of small GTPases and underlines the complexity and diverse roles of small GTPases.

scholarly journals Machine learning classification of new asteroid families members

2020 ◽  
Author(s):  
Valerio Carruba
Keyword(s):  
Machine Learning ◽  
Family Members ◽  
Classification Algorithms ◽  
New Members ◽  
Machine Learning Classification ◽  
New Family ◽  
Robotic Telescope ◽  
Traditional Approaches ◽  
Asteroid Families

<p>Asteroid families are groups of asteroids that are the product of collisions or of the rotational fission of a parent object.  These groups are mainly identified in proper elements or frequencies domains.   Because of robotic telescope surveys, the number of known asteroids has increased from about 10,000 in the early 90's to more than 750,000 nowadays. Traditional approaches for identifying new members of asteroid families, like the hierarchical clustering method (HCM), may   struggle to keep up with the growing rate of new discoveries. Here we used machine learning classification algorithms to identify new family members based on the orbital distribution in proper (a,e,sin(i)) of previously known family constituents. We compared the outcome of nine classification algorithms from stand alone and ensemble approaches.  The Extremely Randomized Trees (ExtraTree) method had the highest precision, enabling to  retrieve up to 97% of family members identified with standard HCM.</p>

scholarly journals Co-ordinated Ras and Rac activity shapes macropinocytic cups and enables phagocytosis of geometrically diverse bacteria

2019 ◽  
Author(s):  
Catherine M. Buckley ◽  
Henderikus Pots ◽  
Aurelie Gueho ◽  
Ben A. Phillips ◽  
Bernd Gilsbach ◽  
...  
Keyword(s):  
Dictyostelium Discoideum ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Extracellular Material ◽  
Multidomain Protein ◽  
Complex Shapes ◽  
Rho Family ◽  
Phagocytic Cups ◽  
Interior Domain ◽  
Professional Phagocyte

AbstractEngulfment of extracellular material by phagocytosis or macropinocytosis depends on the ability of cells to generate specialised cup shaped protrusions. To effectively capture and internalise their targets, these cups are organised into a ring or ruffle of actin-driven protrusion encircling a non-protrusive interior domain. These functional domains depend on the combined activities of multiple Ras and Rho family small GTPases, but how their activities are integrated and differentially regulated over space and time is unknown. Here, we show that the amoeba Dictyostelium discoideum coordinates Ras and Rac activity using the multidomain protein RGBARG (RCC1, RhoGEF, BAR and RasGAP-containing protein). We find RGBARG uses a tripartite mechanism of Ras, Rac and phospholipid interactions to localise at the protruding edge and interface with the interior of both macropinocytic and phagocytic cups. There, RGBARG shapes the protrusion by driving Rac activation at the rim whilst suppressing expansion of the active Ras interior domain. Consequently, cells lacking RGBARG form enlarged, flat interior domains unable to generate large macropinosomes. During phagocytosis, we find that disruption of RGBARG causes a geometry-specific defect in engulfing rod-shaped bacteria and ellipsoidal beads. This demonstrates the importance of co-ordinating small GTPase activities during engulfment of more complex shapes and thus the full physiological range of microbes, and how this is achieved in a model professional phagocyte.

scholarly journals RNA Interference Screening Identifies Novel Roles for RhoBTB1 and RhoBTB3 in Membrane Trafficking Events in Mammalian Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1089 ◽  
Author(s):  
Maeve Long ◽  
Tilen Kranjc ◽  
Margaritha M. Mysior ◽  
Jeremy C. Simpson
Keyword(s):  
Rna Interference ◽  
Golgi Complex ◽  
Membrane Trafficking ◽  
Mammalian Cells ◽  
Rho Gtpase ◽  
Family Members ◽  
Membrane Traffic ◽  
Small Gtpases ◽  
Endomembrane System ◽  
Rho Family

In the endomembrane system of mammalian cells, membrane traffic processes require a high degree of regulation in order to ensure their specificity. The range of molecules that participate in trafficking events is truly vast, and much attention to date has been given to the Rab family of small GTPases. However, in recent years, a role in membrane traffic for members of the Rho GTPase family, in particular Cdc42, has emerged. This prompted us to develop and apply an image-based high-content screen, initially focussing on the Golgi complex, using RNA interference to systematically perturb each of the 21 Rho family members and assess their importance to the overall organisation of this organelle. Analysis of our data revealed previously unreported roles for two atypical Rho family members, RhoBTB1 and RhoBTB3, in membrane traffic events. We find that depletion of RhoBTB3 affects the morphology of the Golgi complex and causes changes in the trafficking speeds of carriers operating at the interface of the Golgi and endoplasmic reticulum. In addition, RhoBTB3 was found to be present on these carriers. Depletion of RhoBTB1 was also found to cause a disturbance to the Golgi architecture, however, this phenotype seems to be linked to endocytosis and retrograde traffic pathways. RhoBTB1 was found to be associated with early endosomal intermediates, and changes in the levels of RhoBTB1 not only caused profound changes to the organisation and distribution of endosomes and lysosomes, but also resulted in defects in the delivery of two different classes of cargo molecules to downstream compartments. Together, our data reveal new roles for these atypical Rho family members in the endomembrane system.

What vibrations tell us about GTPases

2015 ◽  
Vol 396 (2) ◽  
pp. 131-144 ◽  
Author(s):  
Carsten Kötting ◽  
Klaus Gerwert
Keyword(s):  
Small Gtpases ◽  
Small Gtpase ◽  
Attenuated Total Reflection ◽  
Transport Mechanisms ◽  
Spatiotemporal Resolution ◽  
Gtp Hydrolysis ◽  
Time Resolved ◽  
Gtpase Activating Proteins ◽  
Catalytic Mechanisms ◽  
Insight Into

Abstract In this review, we discuss how time-resolved Fourier transform infrared (FTIR) spectroscopy is used to understand how GTP hydrolysis is catalyzed by small GTPases and their cognate GTPase-activating proteins (GAPs). By interaction with small GTPases, GAPs regulate important signal transduction pathways and transport mechanisms in cells. The GTPase reaction terminates signaling and controls transport. Dysfunctions of GTP hydrolysis in these proteins are linked to serious diseases including cancer. Using FTIR, we resolved both the intrinsic and GAP-catalyzed GTPase reaction of the small GTPase Ras with high spatiotemporal resolution and atomic detail. This provided detailed insight into the order of events and how the active site is completed for catalysis. Comparisons of Ras with other small GTPases revealed conservation and variation in the catalytic mechanisms. The approach was extended to more nearly physiological conditions at a membrane. Interactions of membrane-anchored GTPases and their extraction from the membrane are studied using the attenuated total reflection (ATR) technique.

scholarly journals Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells

2000 ◽  
Vol 20 (19) ◽  
pp. 7378-7387 ◽  
Author(s):  
Hironori Katoh ◽  
Hidekazu Yasui ◽  
Yoshiaki Yamaguchi ◽  
Junko Aoki ◽  
Hirotada Fujita ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Morphological Changes ◽  
Cell Types ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Wild Type ◽  
Rho Family ◽  
Constitutively Active

ABSTRACT The Rho family of small GTPases has been implicated in cytoskeletal reorganization and subsequent morphological changes in various cell types. Among them, Rac and Cdc42 have been shown to be involved in neurite outgrowth in neuronal cells. In this study, we examined the role of RhoG, another member of Rho family GTPases, in nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Expression of wild-type RhoG in PC12 cells induced neurite outgrowth in the absence of NGF, and the morphology of wild-type RhoG-expressing cells was similar to that of NGF-differentiated cells. Constitutively active RhoG-transfected cells extended short neurites but developed large lamellipodial or filopodial structures at the tips of neurites. RhoG-induced neurite outgrowth was inhibited by coexpression with dominant-negative Rac1 or Cdc42. In addition, expression of constitutively active RhoG elevated endogenous Rac1 and Cdc42 activities. We also found that the NGF-induced neurite outgrowth was enhanced by expression of wild-type RhoG whereas expression of dominant-negative RhoG suppressed the neurite outgrowth. Furthermore, constitutively active Ras-induced neurite outgrowth was also suppressed by dominant-negative RhoG. Taken together, these results suggest that RhoG is a key regulator in NGF-induced neurite outgrowth, acting downstream of Ras and upstream of Rac1 and Cdc42 in PC12 cells.

scholarly journals The discovery and maturation of peptide biologics targeting the small G-protein Cdc42: A bioblockade for Ras-driven signaling

2020 ◽  
Vol 295 (9) ◽  
pp. 2866-2884 ◽  
Author(s):  
George J. N. Tetley ◽  
Natasha P. Murphy ◽  
Stephane Bonetto ◽  
Gabriela Ivanova-Berndt ◽  
Jefferson Revell ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Inhibitory Effect ◽  
Small Gtpases ◽  
Affinity Maturation ◽  
Small Gtpase ◽  
Ras Signaling ◽  
Cell Interior ◽  
Small G Protein ◽  
A Cell ◽  
Rho Family

Aberrant Ras signaling drives 30% of cancers, and inhibition of the Rho family small GTPase signaling has been shown to combat Ras-driven cancers. Here, we present the discovery of a 16-mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely-related small GTPases. The structure of the tightest binding peptide was solved by NMR, and its binding site on Cdc42 was determined. Addition of a cell-penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signaling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such, they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data add to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.

scholarly journals Machine learning classification of new asteroid families members

2020 ◽  
Vol 496 (1) ◽  
pp. 540-549
Author(s):  
V Carruba ◽  
S Aljbaae ◽  
R C Domingos ◽  
A Lucchini ◽  
P Furlaneto
Keyword(s):  
Machine Learning ◽  
Family Members ◽  
Classification Algorithms ◽  
New Members ◽  
Machine Learning Classification ◽  
New Family ◽  
Robotic Telescope ◽  
Traditional Approaches ◽  
Asteroid Families

ABSTRACT Asteroid families are groups of asteroids that are the product of collisions or of the rotational fission of a parent object. These groups are mainly identified in proper elements or frequencies domains. Because of robotic telescope surveys, the number of known asteroids has increased from ${\simeq}10\, 000$ in the early 1990s to more than $750\, 000$ nowadays. Traditional approaches for identifying new members of asteroid families, like the hierarchical clustering method (HCM), may struggle to keep up with the growing rate of new discoveries. Here we used machine learning classification algorithms to identify new family members based on the orbital distribution in proper (a, e, sin (i)) of previously known family constituents. We compared the outcome of nine classification algorithms from stand-alone and ensemble approaches. The extremely randomized trees (ExtraTree) method had the highest precision, enabling to retrieve up to 97 per cent of family members identified with standard HCM.

scholarly journals The Small GTPases in Fungal Signaling Conservation and Function

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1039
Author(s):  
Mitzuko Dautt-Castro ◽  
Montserrat Rosendo-Vargas ◽  
Sergio Casas-Flores
Keyword(s):  
General Rule ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Nucleotide Exchange ◽  
Plant Interactions ◽  
New Family ◽  
Ras Gtpases ◽  
Guanine Nucleotide Exchange ◽  
Small Proteins ◽  
And Function

Monomeric GTPases, which belong to the Ras superfamily, are small proteins involved in many biological processes. They are fine-tuned regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Several families have been identified in organisms from different kingdoms. Overall, the most studied families are Ras, Rho, Rab, Ran, Arf, and Miro. Recently, a new family named Big Ras GTPases was reported. As a general rule, the proteins of all families have five characteristic motifs (G1–G5), and some specific features for each family have been described. Here, we present an exhaustive analysis of these small GTPase families in fungi, using 56 different genomes belonging to different phyla. For this purpose, we used distinct approaches such as phylogenetics and sequences analysis. The main functions described for monomeric GTPases in fungi include morphogenesis, secondary metabolism, vesicle trafficking, and virulence, which are discussed here. Their participation during fungus–plant interactions is reviewed as well.

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