A Genome-wide Ras-Effector Interaction Network

Kiel, Christina; Foglierini, Mathilde; Kuemmerer, Nico; Beltrão, Pedro; Serrano, Luís

doi:10.1016/j.jmb.2007.05.015

Cited by 38 publications

(49 citation statements)

References 51 publications

(91 reference statements)

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“…3 The suggestion that Di-Ras proteins interact with Arap1, 6 could not be confirmed in vitro either. Hence, Di-Ras proteins have a distinct, Ras-and Rap-independent subset of effectors that remain to be identified.…”

Section: Discussionmentioning

confidence: 97%

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GTPase activity of Di-Ras proteins is stimulated by Rap1GAP proteins

Gasper¹,

Sot²,

Wittinghofer³

2010

Small GTPases

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The Ras family is the largest and most diverse sub-group of Ras-like G proteins. This complexity is further increased by the high number of regulatory Guanine nucleotide exchange Factors (GeFs) and GTPase activating Proteins (GaPs) that target specific members of this subfamily. Di-Ras1 and Di-Ras2 are little characterized members of the Ras-like sub-group with still unidentified regulatory and effector proteins. here we determined the nucleotide binding properties of Di-Ras1/ Di-Ras2. The above nanomolar affinity and the inability to react with members of the cdc25 RasGeF family might suggest that activation does not require a GeF. We identified Rap1GaP1 and Rap1GaP2 as specific GTPase activating proteins of the Di-Ras family. Dual-specificity GaPs of the GaP1 m family could not activate Di-Ras proteins, despite the presence of the required catalytic residue. although Di-Ras proteins share GaPs with Rap G proteins, no common effectors could be identified in vitro.

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Section: Discussionmentioning

confidence: 97%

“…These might include the ArfGAP/RhoGAP protein Arap1. 6 The biological function of Di-Ras1/Di-Ras2 remains unknown. Overexpression of either leads to formation of vacuoles in HEK293T cells suggesting comparable biochemical functions.…”

Section: Introductionmentioning

confidence: 99%

GTPase activity of Di-Ras proteins is stimulated by Rap1GAP proteins

Gasper¹,

Sot²,

Wittinghofer³

2010

Small GTPases

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“…The Ras-binding domains (RBD), such as that found in Raf1, is represented in approximately 50 human gene products (48). The Syx RndBD likely adopts the same type of effector complex as seen for the Raf1-Ras complex (49) judging by mutational analysis of the Syx RndBD (14).…”

Section: Do Other Rnd Interacting Domains Stabilize Rnd3mentioning

confidence: 99%

The GTPase-deficient Rnd Proteins Are Stabilized by Their Effectors

Goh

Manser²

2012

Journal of Biological Chemistry

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Background: Rnds are constitutively active proteins whose regulation is poorly understood. Results: Interaction with Syx or p190 RhoGAP stabilizes Rnds whereas ROCK activity stimulates Rnd3 turnover. Conclusion:The steady-state level of Rnd proteins depends on the availability of cellular effectors that protect them from degradation. Significance: This study uncovers a new mode of feedback regulation for Rnd proteins.

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“…Assuming that similar amino acid sequences have a similar fold and that domains within a similar fold interact in a similar way (Aloy and Russell 2006), it is possible to predict novel proteinprotein interactions based on existing structural information (Kiel et al 2005(Kiel et al , 2007. By generating homology models of proteins with similar sequences, protein design algorithms (Kiel et al 2007) can then be used to calculate the relative interaction energies of related binary interactions. Using this approach, predicted freeenergy values for >3000 possible E2/E3-RING parings were calculated (data provided in Supplemental File 4).…”

Section: True Homology Modeling Of Human E2/e3-ring Interactionsmentioning

confidence: 99%

“…Prediction of free-energy values for different human E2/E3-RING complexes was performed in accordance with previously published methods (Kiel et al 2005(Kiel et al , 2007. As the pdb:1fbv structure was the only available template for modeling the E2/E3-RING with a range of isolated UBC (1i7k, 1x23, 2csv, 2cyx, and 1a3s) or E3-RING (1rmd, 1z6u, and 2ckl) structures.…”

Section: True Homology Modelingmentioning

confidence: 99%

Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network

Markson¹,

Kiel²,

Hyde³

et al. 2009

Genome Res.

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138

151

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In eukaryotic cells the stability and function of many proteins are regulated by the addition of ubiquitin or ubiquitin-like peptides. This process is dependent upon the sequential action of an E1-activating enzyme, an E2-conjugating enzyme, and an E3 ligase. Different combinations of these proteins confer substrate specificity and the form of protein modification. However, combinatorial preferences within ubiquitination networks remain unclear. In this study, yeast two-hybrid (Y2H) screens were combined with true homology modeling methods to generate a high-density map of human E2/E3-RING interactions. These data include 535 experimentally defined novel E2/E3-RING interactions and >1300 E2/E3-RING pairs with more favorable predicted free-energy values than the canonical UBE2L3-CBL complex. The significance of Y2H predictions was assessed by both mutagenesis and functional assays. Significantly, 74/80 (>92%) of Y2H predicted complexes were disrupted by point mutations that inhibit verified E2/E3-RING interactions, and a ;93% correlation was observed between Y2H data and the functional activity of E2/E3-RING complexes in vitro. Analysis of the high-density human E2/E3-RING network reveals complex combinatorial interactions and a strong potential for functional redundancy, especially within E2 families that have undergone evolutionary expansion. Finally, a one-step extended human E2/E3-RING network, containing 2644 proteins and 5087 edges, was assembled to provide a resource for future functional investigations.

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A Genome-wide Ras-Effector Interaction Network

Cited by 38 publications

References 51 publications

GTPase activity of Di-Ras proteins is stimulated by Rap1GAP proteins

GTPase activity of Di-Ras proteins is stimulated by Rap1GAP proteins

The GTPase-deficient Rnd Proteins Are Stabilized by Their Effectors

Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network

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