scholarly journals A Novel Computational Framework to Predict the Impact of a Point Mutation on PDZ Domain Classification

2018 ◽  
Author(s):  
Muhammad Moinuddin ◽  
Wasim Aftab ◽  
Adnan Memic
Keyword(s):  
Usher Syndrome ◽  
Pdz Domain ◽  
Point Mutations ◽  
Similarity Measures ◽  
Bigram Frequency ◽  
Computational Techniques ◽  
Pdz Domains ◽  
Computational Framework ◽  
Class 1 ◽  
The Impact

AbstractPDZ domains represent one of the most common protein homology regions playing key roles in several diseases. Point mutations (PM) in amino acid primary sequence of PDZ domains can alter domain functions by affecting for example, downstream phosphorylation, a pivotal process in biology. Our goal in this present study was to introduce a novel approach to investigate how point mutations within the Class 1, Class 2 and Class 1–2 PDZ domains could affect the changes in binding with their partner ligands and hence affect their classification. We focused on features in PDZ domains of various species including human, rat and mouse. However, our work represents a generic computational framework that could be used to analyze PM in any given PDZ sequence. We have adopted two different approaches to investigate the impact of PM. In the first approach, we have developed a statistical model using bigram frequencies of amino acids and employed six different similarity measures to contrast the bigram frequency distribution of a wild type sequence relevant to its point mutants. In the next approach, we developed a statistical method that incorporates the impact of bigram frequency history associated with each mutational site that we call history weighted conditional change in probabilities. In this PM study, we observed that the history weighted method performs best when compared to all other methods studied in terms of picking up sites in PDZ domain where a PM could flip the class. We anticipate that this method will present a step forward towards computational techniques unveiling PDZ domain point mutants that largely affect the protein-ligand binding, specificity and affinity. We hope that this and future studies could aid therapy in which PDZ mutations have been implicated as the main disease drivers such as the Usher syndrome.

scholarly journals Interactomic affinity profiling by holdup assay: Acetylation and distal residues impact the PDZome-binding specificity of PTEN phosphatase

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244613
Author(s):  
Pau Jané ◽  
Gergő Gógl ◽  
Camille Kostmann ◽  
Goran Bich ◽  
Virginie Girault ◽  
...  
Keyword(s):  
Consensus Sequence ◽  
Pdz Domain ◽  
Pi3k Pathway ◽  
Binding Motif ◽  
Pdz Domains ◽  
Post Translational Modifications ◽  
Binding Profile ◽  
Protein Motifs ◽  
C Terminus ◽  
The Impact

Protein domains often recognize short linear protein motifs composed of a core conserved consensus sequence surrounded by less critical, modulatory positions. PTEN, a lipid phosphatase involved in phosphatidylinositol 3-kinase (PI3K) pathway, contains such a short motif located at the extreme C-terminus capable to recognize PDZ domains. It has been shown that the acetylation of this motif could modulate the interaction with several PDZ domains. Here we used an accurate experimental approach combining high-throughput holdup chromatographic assay and competitive fluorescence polarization technique to measure quantitative binding affinity profiles of the PDZ domain-binding motif (PBM) of PTEN. We substantially extended the previous knowledge towards the 266 known human PDZ domains, generating the full PDZome-binding profile of the PTEN PBM. We confirmed that inclusion of N-terminal flanking residues, acetylation or mutation of a lysine at a modulatory position significantly altered the PDZome-binding profile. A numerical specificity index is also introduced as an attempt to quantify the specificity of a given PBM over the complete PDZome. Our results highlight the impact of modulatory residues and post-translational modifications on PBM interactomes and their specificity.

Impact of low-confidence interactions on computational identification of protein complexes

2020 ◽  
Vol 18 (04) ◽  
pp. 2050025
Author(s):  
Madhusudan Paul ◽  
Ashish Anand
Keyword(s):  
Semantic Similarity ◽  
Protein Complexes ◽  
Similarity Measures ◽  
Disease Diagnosis ◽  
False Positives ◽  
Detection Methods ◽  
Computational Techniques ◽  
Ppi Networks ◽  
Complex Detection ◽  
The Impact

Protein complexes are the cornerstones of most of the biological processes. Identifying protein complexes is crucial in understanding the principles of cellular organization with several important applications, including in disease diagnosis. Several computational techniques have been developed to identify protein complexes from protein–protein interaction (PPI) data (equivalently, from PPI networks). These PPI data have a significant amount of false positives, which is a bottleneck in identifying protein complexes correctly. Gene ontology (GO)-based semantic similarity measures can be used to assign a confidence score to PPIs. Consequently, low-confidence PPIs are highly likely to be false positives. In this paper, we systematically study the impact of low-confidence PPIs on the performance of complex detection methods using GO-based semantic similarity measures. We consider five state-of-the-art complex detection algorithms and nine GO-based similarity measures in the evaluation. We find that each complex detection algorithm significantly improves its performance after the filtration of low-similarity scored PPIs. It is also observed that the percentage improvement and the filtration percentage (of low-confidence PPIs) are highly correlated.

scholarly journals Interactomic affinity profiling by holdup assay: acetylation and distal residues impact the PDZome-binding specificity of PTEN phosphatase

2020 ◽  
Author(s):  
Pau Jané ◽  
Gergő Gógl ◽  
Camille Kostmann ◽  
Goran Bich ◽  
Virginie Girault ◽  
...  
Keyword(s):  
High Throughput ◽  
Experimental Approach ◽  
Consensus Sequence ◽  
Pdz Domain ◽  
Binding Motif ◽  
Pdz Domains ◽  
Post Translational Modifications ◽  
Binding Profile ◽  
Protein Motifs ◽  
The Impact

AbstractProtein domains often recognize short linear protein motifs composed of a core conserved consensus sequence surrounded by less critical, modulatory positions. Here we used an accurate experimental approach combining high-throughput holdup chromatographic assay and fluorescence polarization to measure quantitative binding affinity profiles of the PDZ domain-binding motif (PBM) of PTEN phosphatase towards the 266 known human PDZ domains. Inclusion of N-terminal flanking residues, acetylation or mutation of a lysine at a modulatory position significantly altered the PDZome-binding profile of the PTEN PBM. A specificity index is also introduced to quantify the specificity of a given PBM over the complete PDZome. Our results highlight the impact of modulatory residues and post-translational modifications on PBM interactomes and their specificity.

scholarly journals Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Lin ◽  
Huang Wang ◽  
Decheng Ren ◽  
Yitian Xia ◽  
Guang He ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Vision Loss ◽  
Biochemical Characterization ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Binding Mode ◽  
Lipid Binding ◽  
Membrane Targeting ◽  
Pdz Domains

Usher syndrome (USH) is the leading cause of hereditary hearing–vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

The Impact of Bioconjugation on the Interfacial Activity of a Protein Biosurfactant

2018 ◽  
Author(s):  
Hossam H Tayeb ◽  
Marina Stienecker ◽  
Anton Middelberg ◽  
Frank Sainsbury
Keyword(s):  
Polyethylene Glycol ◽  
Colloidal Stability ◽  
Point Mutations ◽  
Pharmaceutical Formulations ◽  
Industrial Processes ◽  
Parent Molecule ◽  
Site Specific ◽  
Interfacial Activity ◽  
Surface Active ◽  
The Impact

Biosurfactants, are surface active molecules that can be produced by renewable, industrially scalable biologic processes. DAMP4, a designer biosurfactant, enables the modification of interfaces via genetic or chemical fusion to functional moieties. However, bioconjugation of addressable amines introduces heterogeneity that limits the precision of functionalization as well as the resolution of interfacial characterization. Here we designed DAMP4 variants with cysteine point mutations to allow for site-specific bioconjugation. The DAMP4 variants were shown to retain the structural stability and interfacial activity characteristic of the parent molecule, while permitting efficient and specific conjugation of polyethylene glycol (PEG). PEGylation results in a considerable reduction on the interfacial activity of both single and double mutants. Comparison of conjugates with one or two conjugation sites shows that both the number of conjugates as well as the mass of conjugated material impacts the interfacial activity of DAMP4. As a result, the ability of DAMP4 variants with multiple PEG conjugates to impart colloidal stability on peptide-stabilized emulsions is reduced. We suggest that this is due to constraints on the structure of amphiphilic helices at the interface. Specific and efficient bioconjugation permits the exploration and investigation of the interfacial properties of designer protein biosurfactants with molecular precision. Our findings should therefore inform the design and modification of biosurfactants for their increasing use in industrial processes, and nutritional and pharmaceutical formulations.

scholarly journals Seizure outcome in temporal glioblastoma surgery: lobectomy as a supratotal resection regime outclasses conventional gross-total resection

2021 ◽  
Author(s):  
Valeri Borger ◽  
Motaz Hamed ◽  
Inja Ilic ◽  
Anna-Laura Potthoff ◽  
Attila Racz ◽  
...  
Keyword(s):  
Tumor Resection ◽  
Temporal Lobectomy ◽  
Secondary Outcome ◽  
Seizure Outcome ◽  
Seizure Freedom ◽  
Secondary Outcome Measure ◽  
Total Resection ◽  
Class 1 ◽  
Postoperative Seizure ◽  
The Impact

Abstract Introduction The postoperative seizure freedom represents an important secondary outcome measure in glioblastoma surgery. Recently, supra-total glioblastoma resection in terms of anterior temporal lobectomy (ATL) has gained growing attention with regard to superior long-term disease control for temporal-located glioblastoma compared to conventional gross-total resections (GTR). However, the impact of ATL on seizure outcome in these patients is unknown. We therefore analyzed ATL and GTR as differing extents of resection in regard of postoperative seizure control in patients with temporal glioblastoma and preoperative symptomatic seizures. Methods Between 2012 and 2018, 33 patients with preoperative seizures underwent GTR or ATL for temporal glioblastoma at the authors’ institution. Seizure outcome was assessed postoperatively and 6 months after tumor resection according to the International League Against Epilepsy (ILAE) classification and stratified into favorable (ILAE class 1) versus unfavorable (ILAE class 2–6). Results Overall, 23 out of 33 patients (70%) with preoperative seizures achieved favorable seizure outcome following resection of temporal located glioblastoma. For the ATL group, postoperative seizure freedom was present in 13 out of 13 patients (100%). In comparison, respective rates for the GTR group were 10 out of 20 patients (50%) (p = 0.002; OR 27; 95% CI 1.4–515.9). Conclusions ATL in terms of a supra-total resection strategy was associated with superior favorable seizure outcome following temporal glioblastoma resection compared to GTR. Regarding above mentioned survival benefit following ATL compared to GTR, ATL as an aggressive supra-total resection regime might constitute the surgical modality of choice for temporal-located glioblastoma.

scholarly journals Evaluating the effect of compressing algorithms for trajectory similarity and classification problems

2021 ◽  
Author(s):  
Antonios Makris ◽  
Camila Leite da Silva ◽  
Vania Bogorny ◽  
Luis Otavio Alvares ◽  
Jose Antonio Macedo ◽  
...  
Keyword(s):  
Trajectory Analysis ◽  
Similarity Measures ◽  
Classification Problems ◽  
Trajectory Data ◽  
Compression Algorithms ◽  
Time Ratio ◽  
Ratio Speed ◽  
Trajectory Similarity ◽  
Real World Datasets ◽  
The Impact

AbstractDuring the last few years the volumes of the data that synthesize trajectories have expanded to unparalleled quantities. This growth is challenging traditional trajectory analysis approaches and solutions are sought in other domains. In this work, we focus on data compression techniques with the intention to minimize the size of trajectory data, while, at the same time, minimizing the impact on the trajectory analysis methods. To this extent, we evaluate five lossy compression algorithms: Douglas-Peucker (DP), Time Ratio (TR), Speed Based (SP), Time Ratio Speed Based (TR_SP) and Speed Based Time Ratio (SP_TR). The comparison is performed using four distinct real world datasets against six different dynamically assigned thresholds. The effectiveness of the compression is evaluated using classification techniques and similarity measures. The results showed that there is a trade-off between the compression rate and the achieved quality. The is no “best algorithm” for every case and the choice of the proper compression algorithm is an application-dependent process.

Selection of AmpC β-lactamase variants and metallo-β-lactamases leading to ceftolozane/tazobactam and ceftazidime/avibactam-resistance during treatment of MDR/XDR Pseudomonas aeruginosa infections

2021 ◽  
Author(s):  
Alba Ruedas-López ◽  
Isaac Alonso García ◽  
Cristina Lasarte-Monterrubio ◽  
Paula Guijarro-Sánchez ◽  
Eva Gato ◽  
...  
Keyword(s):  
3D Models ◽  
Resistance Mechanisms ◽  
Class 1 ◽  
Long Read ◽  
Cephalosporin Resistance ◽  
One Year ◽  
Clinical Conditions ◽  
Hybrid Assemblies ◽  
Chromosomal Mutations ◽  
The Impact

Infections caused by ceftolozane/tazobactam and ceftazidime/avibactam-resistant P. aeruginosa infections are an emerging concern. We aimed to analyze the underlying ceftolozane/tazobactam and ceftazidime/avibactam resistance mechanisms in all MDR/XDR P. aeruginosa isolates recovered during one year (2020) from patients with a documented P. aeruginosa infection. Fifteen isolates showing ceftolozane/tazobactam and ceftazidime/avibactam resistance were evaluated. Clinical conditions, previous positive cultures and β-lactams received in the previous month were reviewed for each patient. MICs were determined by broth microdilution. MLSTs and resistance mechanisms were determined using short- and long-read WGS. The impact of PDCs on β-lactam resistance was demonstrated by cloning into an ampC -deficient PAO1 derivative (PAOΔC) and construction of 3D models. Genetic support of acquired β-lactamases was determined in silico from high-quality hybrid assemblies. In most cases, the isolates were recovered after treatment with ceftolozane/tazobactam or ceftazidime/avibactam. Seven isolates from different STs owed their β-lactam resistance to chromosomal mutations and all displayed specific substitutions in PDC: Phe121Leu and Gly222Ser, Pro154Leu, Ala201Thr, Gly214Arg, ΔGly203-Glu219 and Glu219Lys. In the other eight isolates, the ST175 clone was overrepresented (6 isolates) and associated with IMP-28 and IMP-13, whereas two ST1284 isolates produced VIM-2. The cloned PDCs conferred enhanced cephalosporin resistance. 3D PDC models revealed rearrangements affecting residues involved in cephalosporin hydrolysis. Carbapenemases were chromosomal (VIM-2) or plasmid-borne (IMP-28, IMP-13), and associated with class-1 integrons located in Tn402-like transposition modules. Our findings highlight that cephalosporin/ß-lactamase inhibitors are potential selectors of MDR/XDR P. aeruginosa strains producing PDC variants or metallo-ß-lactamases. Judicious use of these agents is encouraged.

scholarly journals In Planta Mutagenesis Determines the Functional Regions of the Wheat Puroindoline Proteins

Genetics ◽  
2009 ◽  
Vol 183 (3) ◽  
pp. 853-860 ◽  
Author(s):  
Leila Feiz ◽  
Brian S. Beecher ◽  
John M. Martin ◽  
Michael J. Giroux
Keyword(s):  
Functional Analysis ◽  
Allelic Variation ◽  
Screening Method ◽  
Point Mutations ◽  
Missense Mutations ◽  
Grain Hardness ◽  
In Planta ◽  
Rich Region ◽  
Critical Function ◽  
The Impact

In planta analysis of protein function in a crop plant could lead to improvements in understanding protein structure/function relationships as well as selective agronomic or end product quality improvements. The requirements for successful in planta analysis are a high mutation rate, an efficient screening method, and a trait with high heritability. Two ideal targets for functional analysis are the Puroindoline a and Puroindoline b (Pina and Pinb, respectively) genes, which together compose the wheat (Triticum aestivum L.) Ha locus that controls grain texture and many wheat end-use properties. Puroindolines (PINs) together impart soft texture, and mutations in either PIN result in hard seed texture. Studies of the PINs' mode of action are limited by low allelic variation. To create new Pin alleles and identify critical function-determining regions, Pin point mutations were created in planta via EMS treatment of a soft wheat. Grain hardness of 46 unique PIN missense alleles was then measured using segregating F2:F3 populations. The impact of individual missense alleles upon PIN function, as measured by grain hardness, ranged from neutral (74%) to intermediate to function abolishing. The percentage of function-abolishing mutations among mutations occurring in both PINA and PINB was higher for PINB, indicating that PINB is more critical to overall Ha function. This is contrary to expectations in that PINB is not as well conserved as PINA. All function-abolishing mutations resulted from structure-disrupting mutations or from missense mutations occurring near the Tryptophan-rich region. This study demonstrates the feasibility of in planta functional analysis of wheat proteins and that the Tryptophan-rich region is the most important region of both PINA and PINB.

scholarly journals Examining Socioeconomic and Computational Aspects of Vaccine Pharmacovigilance

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Vasiliki Soldatou ◽  
Anastasios Soldatos ◽  
Theodoros Soldatos
Keyword(s):  
Adverse Event ◽  
Enrichment Analysis ◽  
Vaccine Safety ◽  
Molecular Data ◽  
Adverse Event Reporting ◽  
Computational Techniques ◽  
Behavioral Determinants ◽  
Clinical Patient ◽  
Adverse Event Data ◽  
The Impact

Background. Vaccine pharmacovigilance relates to the detection of adverse events, their assessment, understanding, and prevention, and communication of their risk to the public. These activities can be tedious and long lasting for regulatory authority scientists and may be affected by community practices and public health policies. To better understand underlying challenges, we examined vaccine adverse event reports, assessed whether data-driven techniques can provide additional insight in safety characterization, and wondered on the impact of socioeconomic parameters. Methods. First, we integrated VAERS content with additional sources of drug and molecular data and examined reaction and outcome occurrence by using disproportionality metrics and enrichment analysis. Second, we reviewed social and behavioral determinants that may affect vaccine pharmacovigilance aspects. Results. We describe our experience in processing more than 607000 vaccine adverse event reports and report on the challenges to integrate more than 95500 VAERS medication narratives with structured information about drugs and other therapeutics or supplements. We found that only 12.6% of events were serious, while 8.97% referred to polypharmacy cases. Exacerbation of serious clinical patient outcomes was observed in 8.88% VAERS cases in which drugs may interact with vaccinations or with each other, regardless of vaccine activity interference. Furthermore, we characterized the symptoms reported in those cases and summarized reaction occurrence among vaccine-types. Last, we examine socioeconomic parameters and cost-management features, explore adverse event reporting trends, and highlight perspectives relating to the use and development of digital services, especially in the context of personalized and collaborative health-care. Conclusions. This work provides an informative review of VAERS, identifies challenges and limitations in the processing of vaccine adverse event data, and calls for the better understanding of the socioeconomic landscape pertaining vaccine safety concerns. We expect that adoption of computational techniques for integrated safety assessment and interpretation is key not only to pharmacovigilance practice but also to stakeholders from the entire healthcare system.

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