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3.
Elife ; 92020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32452762

RESUMO

Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Canais Epiteliais de Sódio/metabolismo , Mimetismo Molecular , Peptídeo Hidrolases/metabolismo , Pneumonia Viral/virologia , Proteínas do Envelope Viral/metabolismo , Proteínas Virais/metabolismo , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Canais Epiteliais de Sódio/genética , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Proteólise , Especificidade por Substrato , Proteínas do Envelope Viral/genética , Proteínas Virais/genética
5.
Phys Chem Chem Phys ; 22(16): 8409-8417, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32270834

RESUMO

Metalloproteins are crucial to many biological processes, such as photosynthesis, respiration, and efficient electron transport. Zinc is the most common transition metal found in proteins and is critical for structure, function and stability, however the effects from the electronic properties of a bound zinc ion on electron transfer are not clearly defined. Here, a series of ß-strand and 310-helical peptides, capable of binding Zn2+via suitably positioned His residues, was synthesized and their ability to undergo electron transfer in the presence and absence of Zn2+ studied by electrochemical and computational means. The ß-strand peptide was shown to be conformationally pre-organized, with this geometry maintained on complexation with zinc. Electrochemical studies show a significant increase in charge transport, following binding of the zinc ion to the ß-strand peptide. In contrast, complexation of zinc to the helical peptide disrupts the intramolecular hydrogen bonding network known to facilitate electron transfer and leads to a loss of secondary structure, resulting in a decrease in charge transfer. These experimental and computational studies reveal an interplay, which demonstrates that bound zinc enhances charge transfer by changing the electronic properties of the peptide, and not simply by influencing secondary structure.


Assuntos
Cátions/química , Modelos Químicos , Mimetismo Molecular , Peptídeos/química , Proteínas/química , Oxirredução
7.
Int J Nanomedicine ; 15: 263-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021179

RESUMO

Purpose: Combined superoxide dismutase (SOD)/catalase mimetics have attracted much attention because of their efficacy against reactive oxygen species-associated diseases; however, their application is often limited owing to their poor stability and the absence of favorable grafting sites. To address this, we developed a new class of SOD/catalase mimetics based on hybrid nanoflowers, which exhibit superior stability and possess the desired grafting sites for drugs and endogenous molecules. Methods: In this work, for the first time, we used polynitroxylated human serum albumin (PNA) to mediate the formation of hybrid copper-based nanoflowers. H2O2 depletion and O2 evolution assays were first performed to determine the catalase-like activity of the hybrid nanoflowers. Next, the xanthine oxidase/cytochrome c method was used to assay the SOD-like activity of the nanoflowers. Further characteristics of the nanoflowers were evaluated using scanning electron microscopy (SEM), electron paramagnetic resonance (EPR), and Fourier-transform infrared spectroscopy (FTIR). Operational stability was assessed via the reusability assay. Results: The H2O2 depletion and O2 evolution assays indicated that PNA-incorporated nanoflowers have genuine catalase-like activity. Kinetic analysis revealed that the reactions of the incorporated nanoflowers with H2O2 not only obey Michaelis-Menton kinetics, but that the nanoflowers also possess a higher affinity for H2O2 than that of native catalase. The FTIR spectra corroborated the presence of PNA in the hybrid nanoflowers, while the EPR spectra confirmed the intermolecular interaction of nitroxides bound to the human serum albumin incorporated into the nanoflowers. The remarkable operational reproducibility of the hybrid nanoflowers in catalase-like and SOD-like reactions was verified across successive batches. Conclusion: Herein, a comparison of Michaelis constants showed that the hybrid nanoflower, a catalase mimetics, outperforms the native catalase. Acting as a "better-than-nature" enzyme mimetics, the hybrid nanoflower with superior stability and desired ligand grafting sites will find widespread utilization in the medical sciences.


Assuntos
Catalase/metabolismo , Nanoestruturas/química , Superóxido Dismutase/metabolismo , Catalase/química , Cobre/química , Citocromos c/química , Citocromos c/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Cinética , Microscopia Eletrônica de Varredura , Mimetismo Molecular , Óxidos de Nitrogênio/química , Oxigênio/química , Oxigênio/metabolismo , Reprodutibilidade dos Testes , Albumina Sérica Humana/química , Espectroscopia de Infravermelho com Transformada de Fourier , Superóxido Dismutase/química , Xantina Oxidase/química , Xantina Oxidase/metabolismo
8.
Biochim Biophys Acta Mol Cell Res ; 1867(6): 118674, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32035967

RESUMO

Increased Pur-alpha (Pura) protein levels in animal models alleviate certain cellular symptoms of the disease spectrum amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Pura is a member of the Pur family of evolutionarily conserved guanine-rich polynucleotide binding proteins containing a repeated signature PUR domain of 60-80 amino acids. Here we have employed a synthetic peptide, TZIP, similar to a Pur domain, but with sequence alterations based on a consensus of evolutionarily conserved Pur family binding domains and having an added transporter sequence. A major familial form of ALS/FTD, C9orf72 (C9), is due to a hexanucleotide repeat expansion (HRE) of (GGGGCC), a Pur binding element. We show by circular dichroism that RNA oligonucleotides containing this purine-rich sequence consist largely of parallel G-quadruplexes. TZIP peptide binds this repeat sequence in both DNA and RNA. It binds the RNA element, including the G-quadruplexes, with a high degree of specificity versus a random oligonucleotide. In addition, TZIP binds both linear and G-quadruplex repeat RNA to form higher order G-quadruplex secondary structures. This change in conformational form by Pur-based peptide represents a new mechanism for regulating G quadruplex secondary structure within the C9 repeat. TZIP modulation of C9 RNA structural configuration may alter interaction of the complex with other proteins. This Pur-based mechanism provides new targets for therapy, and it may help to explain Pura alleviation of certain cellular pathological aspects of ALS/FTD.


Assuntos
Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteínas de Ligação a DNA/química , Peptídeos/farmacologia , Fatores de Transcrição/química , Proteína C9orf72/química , Dicroísmo Circular , Expansão das Repetições de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Quadruplex G/efeitos dos fármacos , Humanos , Modelos Moleculares , Mimetismo Molecular , Peptídeos/síntese química , RNA/química , RNA/metabolismo , Termodinâmica , Fatores de Transcrição/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(7): 3509-3517, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32019879

RESUMO

Personalized medicine offers great potential benefits for disease management but requires continuous monitoring of drugs and drug targets. For instance, the therapeutic window for lithium therapy of bipolar disorder is very narrow, and more frequent monitoring of sodium levels could avoid toxicity. In this work, we developed and validated a platform for long-term, continuous monitoring of systemic analyte concentrations in vivo. First, we developed sodium microsensors that circulate directly in the bloodstream. We used "red blood cell mimicry" to achieve long sensor circulation times of up to 2 wk, while being stable, reversible, and sensitive to sodium over physiologically relevant concentration ranges. Second, we developed an external optical reader to detect and quantify the fluorescence activity of the sensors directly in circulation without having to draw blood samples and correlate the measurement with a phantom calibration curve to measure in vivo sodium. The reader design is inherently scalable to larger limbs, species, and potentially even humans. In combination, this platform represents a paradigm for in vivo drug monitoring that we anticipate will have many applications in the future.


Assuntos
Monitoramento de Medicamentos/métodos , Eritrócitos/química , Sódio/sangue , Animais , Circulação Sanguínea , Monitoramento de Medicamentos/instrumentação , Fluorescência , Camundongos , Camundongos Nus , Mimetismo Molecular , Ratos
11.
Immunity ; 52(2): 388-403.e12, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32023489

RESUMO

Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Ebolavirus/imunologia , Glicoproteínas/imunologia , Doença pelo Vírus Ebola/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Quimioterapia Combinada , Epitopos , Feminino , Glicoproteínas/química , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mimetismo Molecular , Conformação Proteica
12.
Nat Commun ; 11(1): 691, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019933

RESUMO

Multicomponent reactions enable the synthesis of large molecular libraries from relatively few inputs. This scalability has led to the broad adoption of these reactions by the pharmaceutical industry. Here, we employ the four-component Ugi reaction to demonstrate that multicomponent reactions can provide a basis for large-scale molecular data storage. Using this combinatorial chemistry we encode more than 1.8 million bits of art historical images, including a Cubist drawing by Picasso. Digital data is written using robotically synthesized libraries of Ugi products, and the files are read back using mass spectrometry. We combine sparse mixture mapping with supervised learning to achieve bit error rates as low as 0.11% for single reads, without library purification. In addition to improved scaling of non-biological molecular data storage, these demonstrations offer an information-centric perspective on the high-throughput synthesis and screening of small-molecule libraries.


Assuntos
Bibliotecas de Moléculas Pequenas/química , Biotecnologia , Espectrometria de Massas , Mimetismo Molecular , Estrutura Molecular , Nanotecnologia , Bibliotecas de Moléculas Pequenas/síntese química
13.
Autoimmun Rev ; 19(3): 102459, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917265

RESUMO

It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.


Assuntos
Antígenos/imunologia , Doenças Autoimunes/imunologia , Proteínas na Dieta/imunologia , Alimentos , Anticorpos/imunologia , Humanos , Sistema Imunitário , Tolerância Imunológica , Mimetismo Molecular
14.
Cell Host Microbe ; 27(1): 129-139.e4, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31901521

RESUMO

Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.


Assuntos
Proteínas de Bactérias/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Mimetismo Molecular/imunologia , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Linhagem Celular , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Humanos , Imunidade Inata , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/imunologia , Salmonella , Transdução de Sinais
15.
PLoS Pathog ; 16(1): e1008231, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905227

RESUMO

Ebola (EBOV) and Marburg (MARV) are members of the Filoviridae family, which continue to emerge and cause sporadic outbreaks of hemorrhagic fever with high mortality rates. Filoviruses utilize their VP40 matrix protein to drive virion assembly and budding, in part, by recruitment of specific WW-domain-bearing host proteins via its conserved PPxY Late (L) domain motif. Here, we screened an array of 115 mammalian, bacterially expressed and purified WW-domains using a PPxY-containing peptide from MARV VP40 (mVP40) to identify novel host interactors. Using this unbiased approach, we identified Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) as novel mVP40 PPxY interactors. YAP and TAZ function as downstream transcriptional effectors of the Hippo signaling pathway that regulates cell proliferation, migration and apoptosis. We demonstrate that ectopic expression of YAP or TAZ along with mVP40 leads to significant inhibition of budding of mVP40 VLPs in a WW-domain/PPxY dependent manner. Moreover, YAP colocalized with mVP40 in the cytoplasm, and inhibition of mVP40 VLP budding was more pronounced when YAP was localized predominantly in the cytoplasm rather than in the nucleus. A key regulator of YAP nuclear/cytoplasmic localization and function is angiomotin (Amot); a multi-PPxY containing protein that strongly interacts with YAP WW-domains. Interestingly, we found that expression of PPxY-containing Amot rescued mVP40 VLP egress from either YAP- or TAZ-mediated inhibition in a PPxY-dependent manner. Importantly, using a stable Amot-knockdown cell line, we found that expression of Amot was critical for efficient egress of mVP40 VLPs as well as egress and spread of authentic MARV in infected cell cultures. In sum, we identified novel negative (YAP/TAZ) and positive (Amot) regulators of MARV VP40-mediated egress, that likely function in part, via competition between host and viral PPxY motifs binding to modular host WW-domains. These findings not only impact our mechanistic understanding of virus budding and spread, but also may impact the development of new antiviral strategies.


Assuntos
Filoviridae/fisiologia , Marburgvirus/fisiologia , Mimetismo Molecular , Proteínas Proto-Oncogênicas c-yes/metabolismo , Proteínas da Matriz Viral/fisiologia , Liberação de Vírus , Sítios de Ligação , Membrana Celular/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas dos Microfilamentos/metabolismo , Modelos Moleculares , Domínios PDZ , Domínios Proteicos , Proteínas Recombinantes de Fusão/metabolismo
16.
Nat Commun ; 11(1): 419, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964889

RESUMO

Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication.


Assuntos
Montagem e Desmontagem da Cromatina/imunologia , Vírus Delta da Hepatite/fisiologia , Antígenos da Hepatite delta/metabolismo , Mimetismo Molecular/imunologia , Proteínas/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Vírus da Hepatite B , Vírus Delta da Hepatite/patogenicidade , Antígenos da Hepatite delta/imunologia , Histonas/imunologia , Histonas/metabolismo , Humanos , Domínios Proteicos/imunologia , Proteínas/genética , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/metabolismo , RNA Viral/metabolismo , Replicação Viral/imunologia
17.
Chem Rec ; 20(1): 10-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30993894

RESUMO

Glycosidases are ubiquitous enzymes involved in a diversity of key biological processes such as energy uptake or cell wall degradation. The design of specific glycosidase inhibitors has been therefore the subject of intense research efforts in academia and pharmaceutical industry. However, until recently, the study of the impact of multivalency on glycosidase inhibition was almost completely neglected. The following account will review our ten year journey on the design of multivalent glycomimetics within our research group, from the discovery of the first strong multivalent effect in glycosidase inhibition to the high-resolution crystal structures of Jack bean α-mannosidase in complex with the multimeric inhibitor displaying the largest binding enhancements reported so far.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/química , Mimetismo Molecular
18.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 49-57, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31828293

RESUMO

Gastric cancer (GC) is one of malignant tumors with high mortality and morbidity in the world. MicroRNA-122 (miR-122) acts as a tumor suppressor in a variety of cancers and has been found to be dominant in gastric adenocarcinoma. However, the specific biological function of miR-122-5p in GC is not completely clear. In this study, we found that miR-122-5p was low-expressed in GC tissues and cell lines by using qRT-PCR. Overexpression of miR-122-5p inhibited the proliferation, migration, and invasion of GC cells by using CCK-8 and transwell assays. On the contrary, downregulation of miR-122-5p promoted the proliferation, migration, and invasion of GC cells. In addition, we found that the expression of LYN, an Src family tyrosine kinase, was inversely correlated with miR-122-5p expression in GC tissues by using western blot analysis, immunohistochemistry, and qRT-PCR assays. Meanwhile, luciferase assay results indicated that LYN is a direct target of miR-122-5p in GC cells. Moreover, silencing LYN expression by its siRNA inhibited the proliferation, migration, and invasion of GC cells. Importantly, overexpression of LYN restored miR-122-5p-mediated inhibition of the proliferation, migration, and invasion of GC cells. Taken together, our results indicated miR-122-5p inhibited the proliferation, migration, and invasion by targeting LYN in GC.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Neoplasias Gástricas/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mimetismo Molecular/genética , Mutação , RNA Interferente Pequeno/genética , Neoplasias Gástricas/patologia , Transfecção
19.
Anal Bioanal Chem ; 412(2): 521-530, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31834448

RESUMO

Nanomaterials that exhibit enzyme-like activity (nanozymes) have attracted significant attention due to their potential for applications in analytical tests and in the biological field. In this study, an enzyme-like nanomaterial is developed by coupling Pt nanoparticles with WO2.72 (Pt/WO2.72). The resultant nanocomposite nanomaterial exhibits peroxidase activity and catalase activity. Moreover, owing to the presence of W6+ and W5+ in WO2.72, Pt/WO2.72 nanoplates demonstrate promise as scavengers of hydroxyl radicals. The Pt/WO2.72 composite nanoplates exhibit excellent peroxidase-like activity for the sensitive colorimetric detection of H2O2 and blood glucose. These Pt/WO2.72 nanoplates are thought to be a promising tool for broad potential applications in biomedicine, biotechnology, and environmental chemistry. Pt nanoparticles anchored WO2.72 nanoplates (Pt/WO2.72) as a multienzyme-like mimetics exhibits peroxidase activity and catalase activity. Furthermore, this composite can be acted scavengers of hydroxyl radicals.


Assuntos
Colorimetria/métodos , Nanopartículas Metálicas/química , Mimetismo Molecular , Nanoestruturas , Óxidos/química , Peroxidase/metabolismo , Platina/química , Tungstênio/química , Radicais Livres/metabolismo , Hemólise , Humanos , Cinética
20.
Proc Natl Acad Sci U S A ; 117(1): 552-562, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871193

RESUMO

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/genética , Antígenos HLA/genética , Mimetismo Molecular/imunologia , Escleroderma Sistêmico/genética , Afro-Americanos/genética , Alelos , Sequência de Aminoácidos/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Autoantígenos/imunologia , Biologia Computacional , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Antígenos HLA/imunologia , Humanos , Masculino , Mimiviridae/imunologia , Phycodnaviridae/imunologia , Estrutura Secundária de Proteína/genética , Medição de Risco , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Homologia de Sequência de Aminoácidos
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