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1.
Adv Clin Chem ; 92: 217-243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31472755

RESUMO

In recent years, proteomics has been used widely in reproductive research in order to understand the molecular mechanisms related to gametes at the cellular level and the role of proteins involved in fertilization. Network and pathway analysis using bioinformatic tools have paved way to obtain a wider picture on the possible pathways associated with the key differentially expressed proteins (DEPs) and its implication in various infertility scenarios. A brief overview of advanced techniques and bioinformatic tools used for reproductive proteomics is presented. Key findings of proteomic-based studies on male and female reproduction are also presented. Furthermore, the chapter sheds light on the cellular pathways and potential biomarkers associated with male and female infertility. Proteomics coupled with bioinformatic analysis provides an ideal platform for non-invasive management of infertility in couples.


Assuntos
Proteínas/metabolismo , Proteômica , Reprodução , Feminino , Humanos , Masculino , Proteínas/análise
2.
Stud Health Technol Inform ; 267: 175-180, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31483270

RESUMO

Protein signaling networks are crucial cornerstones in cellular responses. Deregulation causes various diseases, including cancer. One pathway that is frequently deregulated in cancer is the WNT signaling pathway. It has been shown that WNT signaling is highly context-dependent and the availability of receptors and ligands determines downstream signaling. In order to reveal which signaling pathways are activated by a specific receptor-ligand combination, we overexpressed the non-canonical WNT receptor ROR2 in the human breast cancer cell line MCF-7 and stimulated it with its putative ligand WNT11. Based on characterization of the cells by Reverse Phase Protein Array (RPPA), we integrated the proteomic data by network reconstruction analysis with prior knowledge from a pathway database. Using this approach, we were able to identify novel edges that differed upon ROR2 overexpression and WNT11 stimulation.


Assuntos
Proteínas/metabolismo , Via de Sinalização Wnt , Humanos , Proteômica
3.
Anticancer Res ; 39(9): 4637-4642, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519561

RESUMO

AIM: The aim of this study was to characterize the role of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1 (AMMECR1) in human lung cancer cell lines. MATERIALS AND METHODS: AMMECR1 gene expression was evaluated in four lung cell lines, with A549 then selected for further in-depth examination. To characterize the role of AMMECR1, silencing was achieved utilizing lentivirus-mediated RNA interference, and confirmed by quantitative real-time polymerase chain reaction and western blotting. The impact of AMMECR1 silencing on cellular proliferation was assessed using Celigo-based and MTT assays. Apoptosis was determined using the annexin V-allophycocyanin single staining method. Cell-cycle arrest was assessed by flow cytometry. Finally, colony formation was assessed using Giemsa staining. RESULTS: In A549 cells, AMMECR1 silencing was found to significantly suppress cell proliferation, reduce colony formation, promote apoptosis, and arrest cells in the S and G2/M phases. CONCLUSION: AMMECR1 plays a critical role in cell proliferation, cell-cycle progression, and apoptosis of human lung cancer cells, and may serve as a potential therapeutic target for non-small-cell lung cancer.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Neoplasias Pulmonares/genética , Proteínas/genética , Células A549 , Linhagem Celular Tumoral , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas/metabolismo , RNA Mensageiro/genética
4.
BMC Ophthalmol ; 19(1): 170, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382918

RESUMO

BACKGROUND: To assess bioactive transforming growth factor-ß2 (TGFß2) and secreted frizzled-related protein-1 (SFRP1) levels in aqueous humor (AH) of different types of glaucoma. METHODS: AH samples were obtained immediately before ophthalmic surgery with a 27-gauge needle attached to a microsyringe from 126 eyes (105 patients) divided into five groups: cataract (control), primary open-angle glaucoma (POAG), chronic angle-closure glaucoma (CACG), primary angle-closure suspects (PACS), and acute angle-closure glaucoma (AACG). Bioactive TGFß2 and SFRP1 levels were assayed by ELISA. RESULTS: The concentration of TGFß2 in AH of POAG patients, but not CACG, PACS, or AACG patients, was significantly higher than control eyes. However, within the AACG group, although the TGFß2 levels in AH did not differ significantly from the control level when all AACG patients were grouped together, there were differences when the AACG patients were divided into high and normal intraocular pressure (IOP); TGFß2 of AACG patients with high IOP (> 21 mmHg) was significantly higher than those with normal IOP. AH levels of SFRP1 were not significantly different among the groups. However, a statistical significant, negative correlation between SFRP1 and IOP existed in the POAG group. POAG patients with high IOP had lower levels of SFRP1 than those with normal IOP. In contrast, a significant, positive correlation between SFRP1 level and IOP was detected in the AACG group. AACG patients with high IOP had a higher level of SFRP1 than those with normal IOP. Concentrations of TGFß2 and SFRP1 did not correlate significantly with each other, or with age. CONCLUSIONS: These results indicate that AH levels of TGFß2 and SFRP1 showed different profiles in different types of glaucomas.


Assuntos
Humor Aquoso/metabolismo , Glaucoma de Ângulo Fechado/metabolismo , Glaucoma de Ângulo Aberto/metabolismo , Pressão Intraocular/fisiologia , Proteínas/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Idoso , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Glaucoma de Ângulo Fechado/fisiopatologia , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade
5.
BMC Bioinformatics ; 20(1): 422, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412768

RESUMO

BACKGROUND: One of the main issues in the automated protein function prediction (AFP) problem is the integration of multiple networked data sources. The UNIPred algorithm was thereby proposed to efficiently integrate -in a function-specific fashion- the protein networks by taking into account the imbalance that characterizes protein annotations, and to subsequently predict novel hypotheses about unannotated proteins. UNIPred is publicly available as R code, which might result of limited usage for non-expert users. Moreover, its application requires efforts in the acquisition and preparation of the networks to be integrated. Finally, the UNIPred source code does not handle the visualization of the resulting consensus network, whereas suitable views of the network topology are necessary to explore and interpret existing protein relationships. RESULTS: We address the aforementioned issues by proposing UNIPred-Web, a user-friendly Web tool for the application of the UNIPred algorithm to a variety of biomolecular networks, already supplied by the system, and for the visualization and exploration of protein networks. We support different organisms and different types of networks -e.g., co-expression, shared domains and physical interaction networks. Users are supported in the different phases of the process, ranging from the selection of the networks and the protein function to be predicted, to the navigation of the integrated network. The system also supports the upload of user-defined protein networks. The vertex-centric and the highly interactive approach of UNIPred-Web allow a narrow exploration of specific proteins, and an interactive analysis of large sub-networks with only a few mouse clicks. CONCLUSIONS: UNIPred-Web offers a practical and intuitive (visual) guidance to biologists interested in gaining insights into protein biomolecular functions. UNIPred-Web provides facilities for the integration of networks, and supplies a framework for the imbalance-aware protein network integration of nine organisms, the prediction of thousands of GO protein functions, and a easy-to-use graphical interface for the visual analysis, navigation and interpretation of the integrated networks and of the functional predictions.


Assuntos
Biologia Computacional/métodos , Internet , Mapas de Interação de Proteínas , Proteínas/metabolismo , Software , Algoritmos , Interface Usuário-Computador
6.
Results Probl Cell Differ ; 67: 17-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31435790

RESUMO

Acetylation is among the most prevalent posttranslational modifications in cells and regulates a number of physiological processes such as gene transcription, cell metabolism, and cell signaling. Although initially discovered on nuclear histones, many non-nuclear proteins have subsequently been found to be acetylated as well. The centrosome is the major microtubule-organizing center in most metazoans. Recent proteomic data indicate that a number of proteins in this subcellular compartment are acetylated. This review gives an overview of our current knowledge on protein acetylation at the centrosome and its functional relevance in organelle biology.


Assuntos
Centrossomo/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Acetilação , Animais , Histonas/metabolismo , Humanos , Proteômica
7.
Biol Bull ; 237(1): 1-15, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31441702

RESUMO

The pen, or gladius, of the squid is an internalized shell. It serves as a site of attachment for important muscle groups and as a protective barrier for the visceral organs. The pen's durability and flexibility are derived from its unique composition of chitin and protein. We report the characterization of the structure, development, and composition of pens from Doryteuthis pealeii. The nanofibrils of the polysaccharide ß-chitin are arranged in an aligned configuration in only specific regions of the pen. Chitin is secreted early in development, enabling us to characterize the changes in pen morphology prior to hatching. The chitin and proteins are assembled in the shell sac surrounded by fluid that has a significantly different ionic composition from squid plasma. Two groups of proteins are associated with the pen: those on its surface and those embedded within the pen. Only 20 proteins are identified as embedded within the pen. Embedded proteins are classified into six groups, including chitin associated, protease, protease inhibitors, intracellular, extracellular matrix, and those that are unknown. The pen proteins share many conserved domains with proteins from other chitinous structures. We conclude that the pen is one of the least complex, load-bearing, chitin-rich structures currently known and is amenable to further studies to elucidate natural construction mechanisms using chitin and protein.


Assuntos
Quitina/metabolismo , Decapodiformes/anatomia & histologia , Proteínas/metabolismo , Estruturas Animais/anatomia & histologia , Estruturas Animais/química , Estruturas Animais/crescimento & desenvolvimento , Animais , Decapodiformes/química , Decapodiformes/crescimento & desenvolvimento
9.
Zhonghua Shao Shang Za Zhi ; 35(6): 467-471, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31280543

RESUMO

Metabolic disorder is one of the most obvious pathophysiological characteristics of patients with severe burn or trauma, which leads to high mortality of patients with severe burn or trauma. Metabonomics is a newly developed subject which provides new research concepts and ideas for studying the changes of metabolism in a disease condition. Based on the analysis of group indicators, metabonomic technique not only can systematically study the change rules of metabolites, which helps to further clarify the pathophysiological mechanism of burn or trauma, but also is helpful to find some significant biomarkers with important clinical value so as to provide new insight for the therapy of burn or trauma. This paper reviews the research progress of application of metabonomics in the treatment of severe burn or trauma in recent years.


Assuntos
Queimaduras/terapia , Metabolômica , Proteínas/uso terapêutico , Biomarcadores , Queimaduras/metabolismo , Humanos , Metabolômica/tendências , Proteínas/metabolismo
10.
Anal Bioanal Chem ; 411(21): 5351-5361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267193

RESUMO

Exosomes are membrane-bound vesicles secreted by cells, and contain various important biological molecules, such as lipids, proteins, messenger RNAs, microRNAs, and noncoding RNAs. Emerging evidence demonstrates that proteomic analysis of exosomes is of great significance in studying metabolic diseases, tumor metastasis, immune regulation, and so forth. However, exosome proteomic analysis has high requirements with regard to the purity of collected exosomes. Here recent advances in the methods for isolating exosomes and their applications in proteomic analysis are summarized. Graphical abstract.


Assuntos
Exossomos , Proteômica/métodos , Cromatografia de Afinidade/métodos , Humanos , MicroRNAs/metabolismo , Polietilenoglicóis/química , Proteínas/metabolismo , RNA Mensageiro/metabolismo , RNA não Traduzido/metabolismo
11.
Bioresour Technol ; 291: 121868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31357045

RESUMO

To clarify the adsorption behaviors of typical heavy metals onto sludge extracellular polymeric substances (EPS), the adsorption capacities and mechanisms, as well as the contributions of the different EPS components (proteins, humic acids and polysaccharides), to the adsorption of Zn2+, Cu2+ and Cd2+ were separately explored. Overall, proteins exhibited a relatively high adsorption capacity for the three metals ions, followed by humic acid, whereas least for polysaccharides. The adsorption of Cu2+ and Cd2+ onto proteins, humic acid and polysaccharides fit well to the Freundlich isotherm, whereas Langmuir model was the best fit for Zn2+ bindings onto polysaccharides/humic acid. The binding of Cu2+, Zn2+ and Cd2+ onto the three EPS components was exothermically favorable, and significant electrostatic interactions were observed for the heavy metals sorption onto humic acid and proteins. In addition, the effect of metal ions sorption on the spectrum of the proteins, polysaccharides and humic acid was also explored.


Assuntos
Cádmio/química , Cobre/química , Substâncias Húmicas , Polissacarídeos/química , Proteínas/metabolismo , Esgotos , Zinco/química , Adsorção , Cádmio/metabolismo , Cobre/metabolismo , Proteínas/química , Esgotos/química , Zinco/metabolismo
12.
BMC Bioinformatics ; 20(Suppl 13): 381, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337329

RESUMO

BACKGROUND: How can we obtain fast and high-quality clusters in genome scale bio-networks? Graph clustering is a powerful tool applied on bio-networks to solve various biological problems such as protein complexes detection, disease module detection, and gene function prediction. Especially, MCL (Markov Clustering) has been spotlighted due to its superior performance on bio-networks. MCL, however, is skewed towards finding a large number of very small clusters (size 1-3) and fails to detect many larger clusters (size 10+). To resolve this fragmentation problem, MLR-MCL (Multi-level Regularized MCL) has been developed. MLR-MCL still suffers from the fragmentation and, in cases, unrealistically large clusters are generated. RESULTS: In this paper, we propose PS-MCL (Parallel Shotgun Coarsened MCL), a parallel graph clustering method outperforming MLR-MCL in terms of running time and cluster quality. PS-MCL adopts an efficient coarsening scheme, called SC (Shotgun Coarsening), to improve graph coarsening in MLR-MCL. SC allows merging multiple nodes at a time, which leads to improvement in quality, time and space usage. Also, PS-MCL parallelizes main operations used in MLR-MCL which includes matrix multiplication. CONCLUSIONS: Experiments show that PS-MCL dramatically alleviates the fragmentation problem, and outperforms MLR-MCL in quality and running time. We also show that the running time of PS-MCL is effectively reduced with parallelization.


Assuntos
Algoritmos , Proteínas/metabolismo , Análise por Conglomerados , Cadeias de Markov , Mapas de Interação de Proteínas , Proteínas/química
13.
BMC Bioinformatics ; 20(Suppl 13): 383, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337333

RESUMO

BACKGROUND: Drug repurposing has been motivated to ameliorate low probability of success in drug discovery. For the recent decade, many in silico attempts have received primary attention as a first step to alleviate the high cost and longevity. Such study has taken benefits of abundance, variety, and easy accessibility of pharmaceutical and biomedical data. Utilizing the research friendly environment, in this study, we propose a network-based machine learning algorithm for drug repurposing. Particularly, we show a framework on how to construct a drug network, and how to strengthen the network by employing multiple/heterogeneous types of data. RESULTS: The proposed method consists of three steps. First, we construct a drug network from drug-target protein information. Then, the drug network is reinforced by utilizing drug-drug interaction knowledge on bioactivity and/or medication from literature databases. Through the enhancement, the number of connected nodes and the number of edges between them become more abundant and informative, which can lead to a higher probability of success of in silico drug repurposing. The enhanced network recommends candidate drugs for repurposing through drug scoring. The scoring process utilizes graph-based semi-supervised learning to determine the priority of recommendations. CONCLUSIONS: The drug network is reinforced in terms of the coverage and connections of drugs: the drug coverage increases from 4738 to 5442, and the drug-drug associations as well from 808,752 to 982,361. Along with the network enhancement, drug recommendation becomes more reliable: AUC of 0.89 was achieved lifted from 0.79. For typical cases, 11 recommended drugs were shown for vascular dementia: amantadine, conotoxin GV, tenocyclidine, cycloeucine, etc.


Assuntos
Reposicionamento de Medicamentos/métodos , Preparações Farmacêuticas/química , Área Sob a Curva , Interações de Medicamentos , Humanos , Preparações Farmacêuticas/metabolismo , Proteínas/química , Proteínas/metabolismo , Curva ROC , Aprendizado de Máquina Supervisionado
14.
Medicine (Baltimore) ; 98(28): e15336, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305389

RESUMO

BACKGROUND: Human epididymis protein 4 (HE4) protein has garnered a great degree of interest as a complementary biomarker to carbohydrate antigen 125 (CA125), or even as an independent biomarker for monitoring, diagnosis, and prognostication of ovarian cancer. Its use is currently limited to ovarian cancer. Recent studies have suggested that it could also be used in other types of cancers. METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines was used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and statistical analysis based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence interval [CIs) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If data are insufficient, a narrative line of review will be pursued. DISCUSSION: HE4 protein has been shown to have great potential for clinical use as a diagnostic and prognostic marker in epithelial ovarian cancer (EOC). However, HE4 is not only limited to expression in ovarian cancer, but is also overexpressed in lung and endometrial cancers. The effectiveness of HE4 as a biomarker in cancers (other than EOC) has not yet been studied in the form of a comprehensive systematic review and meta-analysis. The results of this study should allow for expanded use of HE4 as a multiutility biomarker in multiple cancer types, thereby, elevating HE4's value as a cancer biomarker. PROSPERO REGISTRATION: CRD42019120326.


Assuntos
Carcinoma/diagnóstico , Carcinoma/metabolismo , Metanálise como Assunto , Proteínas/metabolismo , Revisão Sistemática como Assunto , Biomarcadores Tumorais/metabolismo , Humanos , Prognóstico , Projetos de Pesquisa
15.
Chem Commun (Camb) ; 55(62): 9188-9191, 2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31305808

RESUMO

The metal salts ubiquitously present in biological samples cause serious ion suppression, capillary clogging and signal fluctuation in ESI/nESI. Herein, a current-limited high voltage polarity reversing approach was applied for the online separation of intrinsic metal ions in biological samples, resulting in the generation of protonated analytes at the nESI tip for mass analysis without interference from salt cations. Stable and durable signals (∼30-60 s) were observed for protonated proteins, peptides and metabolites in complex biological samples, including liquids, solids and viscous samples, even with very high salt concentration (100 mM NaCl), allowing comprehensive tandem MS analysis with on average ca. 5-times higher analyte signal intensities compared to the conventional nESI analysis. Therefore this approach offers improved performance of nESI/ESI for the sensitive molecular analysis of untreated biological samples, opening new possibilities in various disciplines, including biology, medicine, chemistry, life sciences, etc.


Assuntos
Peptídeos/análise , Proteínas/análise , Cloreto de Sódio/química , Íons/análise , Peptídeos/metabolismo , Proteínas/metabolismo , Prótons , Espectrometria de Massas por Ionização por Electrospray/instrumentação
16.
Nat Commun ; 10(1): 2905, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266953

RESUMO

Delivery into mammalian cells remains a significant challenge for many applications of proteins as research tools and therapeutics. We recently reported that the fusion of cargo proteins to a supernegatively charged (-30)GFP enhances encapsulation by cationic lipids and delivery into mammalian cells. To discover polyanionic proteins with optimal delivery properties, we evaluate negatively charged natural human proteins for their ability to deliver proteins into cultured mammalian cells and human primary fibroblasts. Here we discover that ProTα, a small, widely expressed, intrinsically disordered human protein, enables up to ~10-fold more efficient cationic lipid-mediated protein delivery compared to (-30)GFP. ProTα enables efficient delivery at low- to mid-nM concentrations of two unrelated genome editing proteins, Cre recombinase and zinc-finger nucleases, under conditions in which (-30)GFP fusion or cationic lipid alone does not result in substantial activity. ProTα may enable mammalian cell protein delivery applications when delivery potency is limiting.


Assuntos
Edição de Genes/métodos , Lipossomos/química , Proteínas/química , Edição de Genes/instrumentação , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Integrases/química , Integrases/genética , Integrases/metabolismo , Lipossomos/metabolismo , Transporte Proteico , Proteínas/genética , Proteínas/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Nucleases de Dedos de Zinco/química , Nucleases de Dedos de Zinco/genética , Nucleases de Dedos de Zinco/metabolismo
18.
Expert Opin Drug Metab Toxicol ; 15(8): 633-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31274340

RESUMO

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. Areas covered: We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Transporte Biológico , Humanos , Lipídeos/química , Fígado/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ligação Proteica , Proteínas/metabolismo
19.
Eur Biophys J ; 48(6): 559-568, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273390

RESUMO

According to the generalized conformational selection model, ligand binding involves the co-existence of at least two conformers with different ligand-affinities in a dynamical equilibrium. Conformational transitions between them should be guaranteed by intramolecular vibrational dynamics associated to each conformation. These motions are, therefore, related to the biological function of a protein. Positions whose mutations are found to alter these vibrations the most can be defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. In a previous study, we have shown that these positions are evolutionarily conserved. They correspond to buried aliphatic residues mostly localized in regular structured regions of the protein like ß-sheets and α-helices. In the present paper, we perform a network analysis of these key positions for a large dataset of paired protein structures in the ligand-free and ligand-bound form. We observe that networks of interactions between these key positions present larger and more integrated networks with faster transmission of the information. Besides, networks of residues result that are robust to conformational changes. Our results reveal that the conformational diversity of proteins seems to be guaranteed by a network of strongly interconnected key positions rather than individual residues.


Assuntos
Proteínas/química , Proteínas/metabolismo , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Vibração
20.
BMC Bioinformatics ; 20(1): 370, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266445

RESUMO

BACKGROUND: In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases. RESULTS: The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets. CONCLUSIONS: The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.


Assuntos
Anemia de Fanconi/patologia , Aprendizado de Máquina , Bases de Dados Factuais , Anemia de Fanconi/metabolismo , Genômica , Humanos , Fenótipo , Proteínas/metabolismo , Transdução de Sinais
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