Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Peng, Wei; Xu, Junwei; Guan, Xiang; Sun, Yao; Zhang, Xuejun C.; Li, Xuemei; Rao, Zihe

doi:10.1007/s13238-011-1036-z

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…Structures of nucleotide-free complexes of REM-Cdc25 tandems have been described for the RasGEF SOS (31) and the RapGEF EPAC (240), showing that the GTPase-binding surface is entirely comprised within the ␣-helical bowl-shaped Cdc25 domain (FIGURE 2). Accordingly, the Cdc25 domain folds on its own, as seen in Ras GRF1 (100) or RalGPS1a (226), and is sufficient for efficient stimulation of nucleotide exchange (53,100,136,226). Nucleotide dissociation is facilitated by remodeling of the switch 2, which inserts Ala59 near the Mg 2ϩ -binding site and orients Glu62 to form a stabilizing salt bridge with the P-loop lysine (Ras numbering), and by removal of the switch 1 by a steric clash with the GEF (FIGURE 3, A AND B).…”

Section: The Cdc25 Family Of Ras/ral/rapgefsmentioning

confidence: 99%

Regulation of Small GTPases by GEFs, GAPs, and GDIs

Cherfils

Zeghouf

2013

Physiological Reviews

1,025

1,031

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Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. The structures and core mechanisms of representative members of small GTPase regulators from most families have now been elucidated, illuminating their general traits combined with scores of unique features. Recent studies reveal that small GTPase regulators have themselves unexpectedly sophisticated regulatory mechanisms, by which they process cellular signals and build up specific cell responses. These mechanisms include multilayered autoinhibition with stepwise release, feedback loops mediated by the activated GTPase, feed-forward signaling flow between regulators and effectors, and a phosphorylation code for RhoGDIs. The flipside of these highly integrated functions is that they make small GTPase regulators susceptible to biochemical abnormalities that are directly correlated with diseases, notably a striking number of missense mutations in congenital diseases, and susceptible to bacterial mimics of GEFs, GAPs, and GDIs that take command of small GTPases in infections. This review presents an overview of the current knowledge of these many facets of small GTPase regulation.

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Section: The Cdc25 Family Of Ras/ral/rapgefsmentioning

confidence: 99%

Regulation of Small GTPases by GEFs, GAPs, and GDIs

Cherfils

Zeghouf

2013

Physiological Reviews

1,025

1,031

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“…But its relationship with SKCM has not been reported. RALGPS1 activates RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thus regulating various downstream cellular processes [45]. RalA has been reported to be widely activated in human SKCM cell lines and shRNA-mediated knockdown of RalA could inhibit SKCM cell line growth [46].…”

Section: Discussionmentioning

confidence: 99%

Complete epigenomic and genomic analysis of transcriptome modulation within skin cutaneous melanoma

et al. 2020

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Background:Alternative splicing (AS), the mechanism underlying the occurrence of protein diversity, may result in cancer genesis and development when it becomes out of control, as suggested by a growing number of studies. However, systemically analyze of AS events at the genome-wide level for skin cutaneous melanoma (SKCM) is still in a preliminary phase. This study aimed to systemically analyze the bioinformatics of the AS events at a genomewide level using The Cancer Genome Atlas (TCGA) SKCM data. Material/Methods:The SpliceSeq tool was used to analyze the AS profiles for SKCM clinical specimens from the TCGA database. The association between AS events and overall survival was analyzed by Cox regression analysis. AS event intersections and a gene interaction network were established by UpSet plot. A multivariate survival model was used to establish a feature genes prognosis model. Results:A total of 103 SKCM patients with full clinical parameters available were included in this study. We established an AS network that investigated the relationship between AS events and clinical prognosis information. Furthermore, 4 underlying feature genes of SKCM (MCF2L, HARS, TFR2, and RALGPS1) were found in the AS network. We performed function analysis as well as correlation analysis of AS events with gene expression.Using the multivariate survival model, we further confirmed the 4 genes that impacted the classifying SKCM prognosis at the level of AS events as well as gene expression, especially in wild-type SKCM. Conclusion:AS events could be ideal indicators for SKCM prognosis. The key feature gene MCF2L played an important role in wild-type SKCM.

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“…(Fig. S5) The area 2 involved the CDC25 Helical Hairpin (α9 and α10 from 823 to 854) that accommodated the loop between α1 and β2 of Rap [50]. (Fig.…”

Section: Analyses Of Active Conformation Occupancy Mapsmentioning

confidence: 99%

Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

Bufano

Laudette

Blondeau

et al. 2020

J Comput Aided Mol Des

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The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding.

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Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Cited by 4 publications

References 39 publications

Regulation of Small GTPases by GEFs, GAPs, and GDIs

Regulation of Small GTPases by GEFs, GAPs, and GDIs

Complete epigenomic and genomic analysis of transcriptome modulation within skin cutaneous melanoma

Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

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