Enriching the human apoptosis pathway by predicting the structures of protein–protein complexes

Acuner-Ozbabacan, Saliha Ece; Keskin, Özlem; Nussinov, Ruth; Gürsoy, Attila

doi:10.1016/j.jsb.2012.02.002

Cited by 27 publications

(29 citation statements)

References 51 publications

(61 reference statements)

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“…To evaluate the structural basis for dimer formation by Ras proteins, we exploited a powerful template-based protein-protein complex structure prediction algorithm (PRISM) (Acuner Ozbabacan et al, 2012; Aytuna et al, 2005; Kar et al, 2012; Ogmen et al, 2005; Tuncbag et al, 2011; Tuncbag et al, 2012). The list of target PDB codes used for the predictions is provided in Table S1.…”

Section: Resultsmentioning

confidence: 99%

GTP-Dependent K-Ras Dimerization

et al. 2015

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SUMMARY Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping Raf’s, PI3K’s, RalGDS’ and additional effectors’ binding surfaces. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps some effectors’ binding sites. This interface may promote Raf‘s activation. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf’s signaling in cancer.

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Section: Resultsmentioning

confidence: 99%

GTP-Dependent K-Ras Dimerization

et al. 2015

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“…FiberDock assigns a binding energy score by taking van der Waals interactions, partial electrostatics, and hydrogen and disulfide bonds into account (16). An energy score below À10 indicates a favorable interaction (14,17,18). PRISM is much faster than classical docking tools and it achieved almost 100% success in predicting the correct conformation of the complex structure (87 out of 88 cases) (19).…”

Section: Building Structures Of Protein-protein Interaction Complexesmentioning

confidence: 99%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

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Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.

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“…On the basis of our previous studies (34,(53)(54)(55), we set the energy-score cutoff value as À10. Thus, predictions with BES values <À10 are considered to be favorable interactions.…”

Section: Resultsmentioning

confidence: 99%

Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP

Muratcioğlu

Presman

Pooley

et al. 2015

Biophysical Journal

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The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.

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Enriching the human apoptosis pathway by predicting the structures of protein–protein complexes

Cited by 27 publications

References 51 publications

GTP-Dependent K-Ras Dimerization

GTP-Dependent K-Ras Dimerization

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP

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