Accurate disulfide-bonding network predictions improve<i>ab initio</i>structure prediction of cysteine-rich proteins

Yang, Jing; He, Bao Ji; Jang, Richard; Zhang, Yang; Shen, Hong

doi:10.1093/bioinformatics/btv459

Cited by 37 publications

(27 citation statements)

References 54 publications

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“…Therefore, we generated an in silico model to explore its structure and potential functions. The homology model of UBE2O was constructed from the amino acid sequence retrieved from the UniProt database (Q9C0C9) with the i‐tasser (Iterative Threading ASSEmbly Refinement) software . First, the CR2 (551–794) domain and UBC (937–1074) domain were modeled independently with the highest template alignment corresponding to the MZM‐REP domains of Mind bomb 1 (Mib1, PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4XI6) and the UBC domain of baculoviral IAP repeat‐containing protein 6 (BIRC6, PDB ID: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=3CEG), respectively.…”

Section: Homology Model Of Ube2omentioning

confidence: 99%

“…Some cysteine residues may also form disulfide bonds to stabilize the overall structure. Indeed, Cyscon predicts the presence of four possible disulfides (566–585, 598–617, 1020–1025, and 1040–1099) in these two regions . It should be noted that the true UBE2O structure might be different from the modeled one due to the limitation of the homology modeling and the complicity of the cellular environment.…”

Section: Homology Model Of Ube2omentioning

confidence: 99%

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Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

et al. 2018

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The ubiquitin‐proteasome system is an important regulatory machinery involved in proteostasis and cellular signaling. Proteins are ubiquitinated via the concerted action of E1 ubiquitin‐activating enzymes, E2 ubiquitin‐conjugating enzymes, and E3 ubiquitin ligases. Although most of the studies to date focus on the significance of E3 ubiquitin ligases in disease development and therapeutic treatment, recent discoveries suggest that E2 ubiquitin‐conjugating enzymes might also be potential drug targets. The ubiquitin‐conjugating enzyme E2 O (UBE2O), an E3‐independent E2 (i.e. an E2/E3 hybrid enzyme), can directly mediate the ubiquitination of many substrates. These include 5′‐AMP‐activated protein kinase catalytic subunit α2 (AMPKα2), tumor suppressor ubiquitin carboxyl‐terminal hydrolase BAP1, mixed‐lineage leukemia (MLL) protein, SMAD family member 6 (SMAD6), transcription factor c‐Maf and aryl hydrocarbon receptor nuclear translocator‐like protein 1 (ARNTL or BMAL1), and free ribosomal proteins, which are ubiquitinated in distinct ways, thereby associating UBE2O with a variety of biological functions. Furthermore, UBE2O is frequently amplified or mutated in multiple cancers, and its high expression is associated with low survival rate of gastric, lung, breast, and prostate cancer patients. However, the molecular mechanisms by which UBE2O contributes to tumor initiation and progression are not fully elucidated. This review focuses on emerging insights from genetics, biochemistry, and cell biology to explore the biological functions of UBE2O and its therapeutic potential.

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Section: Homology Model Of Ube2omentioning

confidence: 99%

Section: Homology Model Of Ube2omentioning

confidence: 99%

Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

et al. 2018

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“…Based on the determined TMHs, the prediction of TMH–TMH residue contacts can provide crucial spatial constraints for accurately modeling tertiary structures of membrane proteins [ 15 , 20 ]. The MemBrain-Contact prediction module is constructed by combining statistical machine learning algorithms and biological residue coevolution analysis from multiple sequence alignments as shown in Fig.…”

Section: Membrain Prediction Functionsmentioning

confidence: 99%

MemBrain: An Easy-to-Use Online Webserver for Transmembrane Protein Structure Prediction

et al. 2017

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Membrane proteins are an important kind of proteins embedded in the membranes of cells and play crucial roles in living organisms, such as ion channels, transporters, receptors. Because it is difficult to determinate the membrane protein’s structure by wet-lab experiments, accurate and fast amino acid sequence-based computational methods are highly desired. In this paper, we report an online prediction tool called MemBrain, whose input is the amino acid sequence. MemBrain consists of specialized modules for predicting transmembrane helices, residue–residue contacts and relative accessible surface area of α-helical membrane proteins. MemBrain achieves a prediction accuracy of 97.9% of A TMH, 87.1% of A P, 3.2 ± 3.0 of N-score, 3.1 ± 2.8 of C-score. MemBrain-Contact obtains 62%/64.1% prediction accuracy on training and independent dataset on top L/5 contact prediction, respectively. And MemBrain-Rasa achieves Pearson correlation coefficient of 0.733 and its mean absolute error of 13.593. These prediction results provide valuable hints for revealing the structure and function of membrane proteins. MemBrain web server is free for academic use and available at www.csbio.sjtu.edu.cn/bioinf/MemBrain/.

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“…These experiments support the hypothesis that [R273C]p53 self-assembly is mediated by disulphide bond as shown infigure S9. We have also verified the disulphide bond partners in WTp53 and [R273C]p53 using DIANNA server (Figure S9)(59,60).Molecular dynamics simulations. We next probed the aggregation of p53 variant proteins in-silico us-ing all-atom MD simulations.…”

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confidence: 79%

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

Garg

Hazra

Sannigrahi

et al. 2019

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Mutations in p53 protein, especially in the DNA binding domain is one of the major hallmarks of cancer. The R273 position is a DNA contact position and has several oncogenic variants. Surprisingly, cancer patients carrying different mutant-variants of R273 in p53 have different survival rates indicating that the DNA contact inhibition may not be the sole reason for reduced survival with R273 variants.Here, we probed the structural properties of three major oncogenic variants of the R273: ([R273L],[R273H], and [R273C])p53. Using a series of biophysical, biochemical and theoretical simulation studies, we observe that these oncogenic variants of the p53 not only suffer a loss in DNA binding, but also show distinct structural stabilty, aggregation and toxicity profiles. [R273C]p53 shows maximum amyloidogenicity while [R273L]p53 shows maximum aggregation. Further probe in the aggregation mechanism show that [R273C]p53 aggregation is disulphide mediated whereas hydrophobic interactions dominate self-assembly in [R273L]p53. MD simulation studies clearly show that α-helical intermediates are observed in [R273C]p53 whereas β-sheets are observed for [R273L]p53. Our study indicates that each of the R273 variant has its own distinct property of stability and self-assembly, the molecular basis of which, may lead to different types of cancer pathogenesis in vivo. These studies will aid the design of therapeutic strategies for cancer using residue specific or process specific protein aggregation as target.Statement of significance. The present work stems from an interesting observation that genetic mutations that results in switching of one amino acid to different variants at the same codon show different cancer cell progression. We are trying to understand the molecular reason behind the different gain-offunction opted by these variants. With the help of biophysical and biochemical experiments, and computational studies we have observed that the different thermal stability, unique mechanism of unfolding and self-assembly might be one of the crucial parameters for their different oncogenic effect. These studies thus call for the need of developing therapeutic strategies that consider the resultant mutantvariant as a target rather than mutation position. This is an important lead towards the understanding of cancer.cate that specific therapeutic strategies that precisely target the additional effect of the mutation apart from compromised DNA binding is also required for cancer management and cure.

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Accurate disulfide-bonding network predictions improveab initiostructure prediction of cysteine-rich proteins

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 37 publications

References 54 publications

Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

MemBrain: An Easy-to-Use Online Webserver for Transmembrane Protein Structure Prediction

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

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