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1.
Adv Exp Med Biol ; 1306: 41-59, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33959905

RESUMEN

Cardiac troponin T (cTnT) is a sensitive and specific biomarker for detecting cardiac muscle injury. Its concentration in blood can be significantly elevated outside the normal reference range under several pathophysiological conditions. The classical analytical method in routine clinical analysis to detect cTnT in serum or plasma is a single commercial immunoassay, which is designed to quantify the intact cTnT molecule. The targeted epitopes are located in the central region of the cTnT molecule. However, in blood cTnT exists in different biomolecular complexes and proteoforms: bound (to cardiac troponin subunits or to immunoglobulins) or unbound (as intact protein or as proteolytic proteoforms). While proteolysis is a principal posttranslational modification (PTM), other confirmed PTMs of the proteoforms include N-terminal initiator methionine removal, N-acetylation, O-phosphorylation, O-(N-acetyl)-glucosaminylation, N(ɛ)-(carboxymethyl)lysine modification and citrullination. The immunoassay probably detects several of those cTnT biomolecular complexes and proteoforms, as long as they have the centrally targeted epitopes in common. While analytical cTnT immunoreactivity has been studied predominantly in blood, it can also be detected in urine, although it is unclear in which proteoform cTnT immunoreactivity is present in urine. This review presents an overview of the current knowledge on the pathophysiological lifecycle of cTnT. It provides insight into the impact of PTMs, not only on the analytical immunoreactivity, but also on the excretion of cTnT in urine as one of the waste routes in that lifecycle. Accordingly, and after isolating the proteoforms from urine of patients suffering from proteinuria and acute myocardial infarction, the structures of some possible cTnT proteoforms are reconstructed using mass spectrometry and presented.


Asunto(s)
Infarto del Miocardio , Troponina T , Humanos , Fosforilación , Procesamiento Proteico-Postraduccional , Proteolisis , Troponina T/metabolismo
2.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33946341

RESUMEN

Platelets are components of the blood that are highly reactive, and they quickly respond to multiple physiological and pathophysiological processes. In the last decade, it became clear that platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity. Protein composition, localization, and activity are crucial for platelet function and regulation. The current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational modifications, and monitor platelet activity during drug treatments. This review focuses on the role of proteomics in understanding the molecular basics of the classical and newly emerging functions of platelets. including the recently described role of platelets in immunology and the development of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed.


Asunto(s)
Plaquetas/metabolismo , Espectrometría de Masas/métodos , Pruebas de Función Plaquetaria/métodos , Proteómica/métodos , Animales , Plaquetas/citología , Plaquetas/inmunología , /metabolismo , Humanos , Transfusión de Plaquetas , Procesamiento Proteico-Postraduccional , Transducción de Señal , Medicina Transfusional/métodos
3.
Yi Chuan ; 43(4): 323-339, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33972207

RESUMEN

Plant homeodomain (PHD) is a class of transcription factor in the Zinc finger domain family. The most important function of which is to recognize various histone modifications, including histone methylation and acetylation, etc. They can also bind to DNA. Proteins with PHD domains, some of which possess histone modification enzyme activity, or can interact with histone modification enzymes, and some are associated with DNA methylation, with E3 ubiquitin ligase activity, or even can be chromatin remodeling factors. As transcriptional regulators, they play an important role in plant growth and development. In this review, we summarize the structural features and substrate binding specificity of PHD domains (including H3K4me3/0, H3K9me3, H3R2, H3K14ac) and DNA, the conservation of plant PHD domain in evolution, the molecular mechanism of known PHD domain-containing proteins in plants, providing a reference for further understanding of the involvement of these proteins during plant growth and development.


Asunto(s)
Proteínas de Homeodominio , Dedos de Zinc PHD , Metilación , Unión Proteica , Procesamiento Proteico-Postraduccional , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
4.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800121

RESUMEN

Nitrotyrosine, which is generated by numerous reactive nitrogen species, is a type of protein post-translational modification. Identification of site-specific nitration modification on tyrosine is a prerequisite to understanding the molecular function of nitrated proteins. Thanks to the progress of machine learning, computational prediction can play a vital role before the biological experimentation. Herein, we developed a computational predictor PredNTS by integrating multiple sequence features including K-mer, composition of k-spaced amino acid pairs (CKSAAP), AAindex, and binary encoding schemes. The important features were selected by the recursive feature elimination approach using a random forest classifier. Finally, we linearly combined the successive random forest (RF) probability scores generated by the different, single encoding-employing RF models. The resultant PredNTS predictor achieved an area under a curve (AUC) of 0.910 using five-fold cross validation. It outperformed the existing predictors on a comprehensive and independent dataset. Furthermore, we investigated several machine learning algorithms to demonstrate the superiority of the employed RF algorithm. The PredNTS is a useful computational resource for the prediction of nitrotyrosine sites. The web-application with the curated datasets of the PredNTS is publicly available.


Asunto(s)
Biología Computacional , Aprendizaje Automático , Procesamiento Proteico-Postraduccional , Proteínas/genética , Análisis de Secuencia de Proteína , Máquina de Vectores de Soporte , Tirosina/análogos & derivados , Tirosina/genética
5.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803458

RESUMEN

Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate in the widespread changes of gene expression that characterize the metastatic phenotype. At the chromatin level, active and repressive histone post-translational modifications (PTM) in association with pleiotropic transcription factors regulate pivotal genes involved in the initiation of the EMT process as well as in intravasation and anoikis resistance, playing a central role in the progression of tumors. Herein, we discuss the main epigenetic mechanisms associated with the different steps of metastatic process, focusing in particular on the prominent role of histone modifications and the modifying enzymes that mediate transcriptional regulation of genes associated with tumor progression. We further discuss the development of novel treatment strategies targeting the reversibility of histone modifications and highlight their importance in the future of cancer therapy.


Asunto(s)
Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Humanos , Metástasis de la Neoplasia , Neoplasias/patología
6.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803872

RESUMEN

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a highly aggressive malignancy, with poorer prognosis in infants than in adults. A genetic signature has been associated with this outcome but, remarkably, leukemogenesis is commonly triggered by genetic alterations of embryonic origin that involve the deregulation of chromatin remodelers. This review considers in depth how the alteration of epigenetic profiles (at DNA and histone levels) induces an aberrant phenotype in B lymphocyte progenitors by modulating the oncogenic drivers and tumor suppressors involved in key cancer hallmarks. DNA methylation patterns have been widely studied in BCP-ALL and their correlation with survival has been established. However, the effect of methylation on histone residues can be very different. For instance, methyltransferase KMT2A gene participates in chromosomal rearrangements with several partners, imposing an altered pattern of methylated H3K4 and H3K79 residues, enhancing oncogene promoter activation, and conferring a worse outcome on affected infants. In parallel, acetylation processes provide an additional layer of epigenetic regulation and can alter the chromatin conformation, enabling the binding of regulatory factors. Therefore, an integrated knowledge of all epigenetic disorders is essential to understand the molecular basis of BCP-ALL and to identify novel entry points that can be exploited to improve therapeutic options and disease prognosis.


Asunto(s)
Epigénesis Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Metilación de ADN/genética , Regulación Leucémica de la Expresión Génica , Histonas/metabolismo , Humanos , Lactante , Procesamiento Proteico-Postraduccional
7.
Nat Commun ; 12(1): 2043, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824312

RESUMEN

The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.


Asunto(s)
Proteínas Portadoras/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Biocatálisis , Resistencia a Antineoplásicos , Células HCT116 , Células HEK293 , Humanos , Lisina/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Unión Proteica , Procesamiento Proteico-Postraduccional , Estabilidad Proteica , ARN Interferente Pequeño/metabolismo , Especificidad por Sustrato , Enzimas Ubiquitina-Conjugadoras/metabolismo
8.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804149

RESUMEN

In the last few decades, the newly emerging field of epigenetic regulation of glycosylation acquired more importance because it is unraveling physiological and pathological mechanisms related to glycan functions. Glycosylation is a complex process in which proteins and lipids are modified by the attachment of monosaccharides. The main actors in this kind of modification are the glycoenzymes, which are translated from glycosylation-related genes (or glycogenes). The expression of glycogenes is regulated by transcription factors and epigenetic mechanisms (mainly DNA methylation, histone acetylation and noncoding RNAs). This review focuses only on these last ones, in relation to cancer and other diseases, such as inflammatory bowel disease and IgA1 nephropathy. In fact, it is clear that a deeper knowledge in the fine-tuning of glycogenes is essential for acquiring new insights in the glycan field, especially if this could be useful for finding novel and personalized therapeutics.


Asunto(s)
Epigénesis Genética/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional/genética , ARN no Traducido/genética , Acetilación , Metilación de ADN/genética , Glicosilación , Humanos , Inmunoglobulina A/genética , Neoplasias/metabolismo , Polisacáridos/genética
9.
BMC Bioinformatics ; 22(1): 171, 2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33789579

RESUMEN

BACKGROUND: Protein post-translational modification (PTM) is a key issue to investigate the mechanism of protein's function. With the rapid development of proteomics technology, a large amount of protein sequence data has been generated, which highlights the importance of the in-depth study and analysis of PTMs in proteins. METHOD: We proposed a new multi-classification machine learning pipeline MultiLyGAN to identity seven types of lysine modified sites. Using eight different sequential and five structural construction methods, 1497 valid features were remained after the filtering by Pearson correlation coefficient. To solve the data imbalance problem, Conditional Generative Adversarial Network (CGAN) and Conditional Wasserstein Generative Adversarial Network (CWGAN), two influential deep generative methods were leveraged and compared to generate new samples for the types with fewer samples. Finally, random forest algorithm was utilized to predict seven categories. RESULTS: In the tenfold cross-validation, accuracy (Acc) and Matthews correlation coefficient (MCC) were 0.8589 and 0.8376, respectively. In the independent test, Acc and MCC were 0.8549 and 0.8330, respectively. The results indicated that CWGAN better solved the existing data imbalance and stabilized the training error. Alternatively, an accumulated feature importance analysis reported that CKSAAP, PWM and structural features were the three most important feature-encoding schemes. MultiLyGAN can be found at https://github.com/Lab-Xu/MultiLyGAN . CONCLUSIONS: The CWGAN greatly improved the predictive performance in all experiments. Features derived from CKSAAP, PWM and structure schemes are the most informative and had the greatest contribution to the prediction of PTM.


Asunto(s)
Lisina , Procesamiento Proteico-Postraduccional , Proteínas , Algoritmos , Lisina/metabolismo , Aprendizaje Automático , Proteínas/genética
10.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33804825

RESUMEN

The addition of nutrients and accumulation of metabolites in a fed-batch culture of Chinese hamster ovary (CHO) cells leads to an increase in extracellular osmolality in late stage culture. Herein, we explore the effect of osmolality on CHO cell growth, specific monoclonal antibody (mAb) productivity and glycosylation achieved with the addition of NaCl or the supplementation of a commercial feed. Although both methods lead to an increase in specific antibody productivity, they have different effects on cell growth and antibody production. Osmolality modulation using NaCl up to 470 mOsm kg-1 had a consistently positive effect on specific antibody productivity and titre. The addition of the commercial feed achieved variable results: specific mAb productivity was increased, yet cell growth rate was significantly compromised at high osmolality values. As a result, Feed C addition to 410 mOsm kg-1 was the only condition that achieved a significantly higher mAb titre compared to the control. Additionally, Feed C supplementation resulted in a significant reduction in galactosylated antibody structures. Cell volume was found to be positively correlated to osmolality; however, osmolality alone could not account for observed changes in average cell diameter without considering cell cycle variations. These results help delineate the overall effect of osmolality on titre and highlight the potentially negative effect of overfeeding on cell growth.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Tamaño de la Célula , Concentración Osmolar , Procesamiento Proteico-Postraduccional , Animales , Células CHO , Proliferación Celular , Cricetinae , Cricetulus , Glicosilación
11.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810246

RESUMEN

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.


Asunto(s)
Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/inmunología , Procesamiento Proteico-Postraduccional , Ácidos Siálicos/metabolismo , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/terapia , Humanos , Inmunofenotipificación/métodos , Medicina de Precisión/métodos , Ácidos Siálicos/inmunología
12.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806791

RESUMEN

The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest.


Asunto(s)
Antibacterianos/farmacología , Bacteriocinas/farmacología , Péptidos/farmacología , Antibacterianos/química , Antifúngicos/farmacología , Bacteriocinas/química , Biopelículas/efectos de los fármacos , Clostridiales/metabolismo , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/microbiología , Clostridium perfringens/efectos de los fármacos , Humanos , Péptidos/química , Procesamiento Proteico-Postraduccional
13.
Nat Commun ; 12(1): 2426, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893288

RESUMEN

To adapt to fluctuating protein folding loads in the endoplasmic reticulum (ER), the Hsp70 chaperone BiP is reversibly modified with adenosine monophosphate (AMP) by the ER-resident Fic-enzyme FICD/HYPE. The structural basis for BiP binding and AMPylation by FICD has remained elusive due to the transient nature of the enzyme-substrate-complex. Here, we use thiol-reactive derivatives of the cosubstrate adenosine triphosphate (ATP) to covalently stabilize the transient FICD:BiP complex and determine its crystal structure. The complex reveals that the TPR-motifs of FICD bind specifically to the conserved hydrophobic linker of BiP and thus mediate specificity for the domain-docked conformation of BiP. Furthermore, we show that both AMPylation and deAMPylation of BiP are not directly regulated by the presence of unfolded proteins. Together, combining chemical biology, crystallography and biochemistry, our study provides structural insights into a key regulatory mechanism that safeguards ER homeostasis.


Asunto(s)
Proteínas de Choque Térmico/metabolismo , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Procesamiento Proteico-Postraduccional , Repeticiones de Tetratricopéptidos , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Retículo Endoplásmico/metabolismo , Células HEK293 , Proteínas de Choque Térmico/química , Homeostasis , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Simulación de Dinámica Molecular , Nucleotidiltransferasas/química , Nucleotidiltransferasas/genética , Unión Proteica , Conformación Proteica , Especificidad por Sustrato
14.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33923616

RESUMEN

DNA double-strand breaks (DSBs) are accidental lesions generated by various endogenous or exogenous stresses. DSBs are also genetically programmed events during the V(D)J recombination process, meiosis, or other genome rearrangements, and they are intentionally generated to kill cancer during chemo- and radiotherapy. Most DSBs are processed in mammalian cells by the classical nonhomologous end-joining (c-NHEJ) pathway. Understanding the molecular basis of c-NHEJ has major outcomes in several fields, including radiobiology, cancer therapy, immune disease, and genome editing. The heterodimer Ku70/80 (Ku) is a central actor of the c-NHEJ as it rapidly recognizes broken DNA ends in the cell and protects them from nuclease activity. It subsequently recruits many c-NHEJ effectors, including nucleases, polymerases, and the DNA ligase 4 complex. Beyond its DNA repair function, Ku is also involved in several other DNA metabolism processes. Here, we review the structural and functional data on the DNA and RNA recognition properties of Ku implicated in DNA repair and in telomeres maintenance.


Asunto(s)
Autoantígeno Ku/metabolismo , Animales , Reparación del ADN , Evolución Molecular , Humanos , Autoantígeno Ku/química , Autoantígeno Ku/genética , Procesamiento Proteico-Postraduccional
15.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33807238

RESUMEN

The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein-Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Remarkably, we observed that the commensal gut microbiota composition in a cohort of RSTS patients is significantly depleted in butyrate-producing bacteria compared to healthy siblings. We demonstrate that the effects of butyrate and the differences in microbiota composition are conserved in a Drosophila melanogaster mutant for CBP, enabling future dissection of the gut-host interactions in an in vivo RSTS model. This study sheds light on microbiota composition in a chromatinopathy, paving the way for novel therapeutic interventions.


Asunto(s)
Butiratos/metabolismo , Síndrome de Rubinstein-Taybi/metabolismo , Síndrome de Rubinstein-Taybi/microbiología , Acetilación , Adolescente , Animales , Butiratos/farmacología , Proteína de Unión a CREB/metabolismo , Niño , Preescolar , Estudios de Cohortes , Modelos Animales de Enfermedad , Drosophila melanogaster/metabolismo , Proteína p300 Asociada a E1A/metabolismo , Ácidos Grasos Volátiles/metabolismo , Ácidos Grasos Volátiles/fisiología , Femenino , Microbioma Gastrointestinal/fisiología , Histona Acetiltransferasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Mutación , Procesamiento Proteico-Postraduccional , Factores de Transcripción p300-CBP/metabolismo
16.
Molecules ; 26(7)2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33918234

RESUMEN

Emiliania huxleyi is a cosmopolitan coccolithophore that plays an essential role in global carbon and sulfur cycling, and contributes to marine cloud formation and climate regulation. Previously, the proteomic profile of Emiliania huxleyi was investigated using a three-dimensional separation strategy combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The current study reuses the MS/MS spectra obtained, for the global discovery of post-translational modifications (PTMs) in this species without specific enrichment methods. Twenty-five different PTM types were examined using Trans-Proteomic Pipeline (Comet and PeptideProphet). Overall, 13,483 PTMs were identified in 7421 proteins. Methylation was the most frequent PTM with more than 2800 modified sites, and lysine was the most frequently modified amino acid with more than 4000 PTMs. The number of proteins identified increased by 22.5% to 18,780 after performing the PTM search. Compared to intact peptides, the intensities of some modified peptides were superior or equivalent. The intensities of some proteins increased dramatically after the PTM search. Gene ontology analysis revealed that protein persulfidation was related to photosynthesis in Emiliania huxleyi. Additionally, various membrane proteins were found to be phosphorylated. Thus, our global PTM discovery platform provides an overview of PTMs in the species and prompts further studies to uncover their biological functions. The combination of a three-dimensional separation method with global PTM search is a promising approach for the identification and discovery of PTMs in other species.


Asunto(s)
Haptophyta/química , Procesamiento Proteico-Postraduccional , Ontología de Genes , Metilación , Péptidos/química , Fosforilación , Proteínas/química , Espectrometría de Masas en Tándem
17.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799890

RESUMEN

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also contribute to the cellular response to viral infections. All domains of the human immunodeficiency virus type 1 (HIV-1) Gag precursor of 55-kDa (Pr55Gag), which is the central actor for viral RNA specific recruitment and genome packaging, are post-translationally modified. In this review, we summarize the current knowledge about HIV-1 Pr55Gag PTMs such as myristoylation, phosphorylation, ubiquitination, sumoylation, methylation, and ISGylation in order to figure out how these modifications affect the precursor functions and viral replication. Indeed, in HIV-1, PTMs regulate the precursor trafficking between cell compartments and its anchoring at the plasma membrane, where viral assembly occurs. Interestingly, PTMs also allow Pr55Gag to hijack the cell machinery to achieve viral budding as they drive recognition between viral proteins or cellular components such as the ESCRT machinery. Finally, we will describe and compare PTMs of several other retroviral Gag proteins to give a global overview of their role in the retroviral life cycle.


Asunto(s)
VIH-1/metabolismo , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , ARN Viral/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo , Membrana Celular/metabolismo , Membrana Celular/virología , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , VIH-1/genética , Humanos , Precursores de Proteínas/genética , ARN Viral/genética , Ensamble de Virus/genética , Replicación Viral/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética
18.
Nat Commun ; 12(1): 2257, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33859198

RESUMEN

Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1ß (MIP-1ß) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.


Asunto(s)
Antivirales/farmacología , Materiales Biomiméticos/química , Biomimética/métodos , Quimiocina CCL4/farmacología , Infecciones por VIH/tratamiento farmacológico , Aminas/química , Antivirales/química , Línea Celular Tumoral , Quimiocina CCL4/química , Quimiocina CCL4/genética , Quimiocina CCL4/aislamiento & purificación , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Mioglobina/química , Oxidación-Reducción , Procesamiento Proteico-Postraduccional , Quinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/química , Ubiquitina/química , Replicación Viral/efectos de los fármacos
19.
BMC Genomics ; 22(1): 255, 2021 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-33838656

RESUMEN

BACKGROUND: Lysine succinylation is a naturally occurring post-translational modification (PTM) that is ubiquitous in organisms. Lysine succinylation plays important roles in regulating protein structure and function as well as cellular metabolism. Global lysine succinylation at the proteomic level has been identified in a variety of species; however, limited information on lysine succinylation in plant species, especially paper mulberry, is available. Paper mulberry is not only an important plant in traditional Chinese medicine, but it is also a tree species with significant economic value. Paper mulberry is found in the temperate and tropical zones of China. The present study analyzed the effects of lysine succinylation on the growth, development, and physiology of paper mulberry. RESULTS: A total of 2097 lysine succinylation sites were identified in 935 proteins associated with the citric acid cycle (TCA cycle), glyoxylic acid and dicarboxylic acid metabolism, ribosomes and oxidative phosphorylation; these pathways play a role in carbon fixation in photosynthetic organisms and may be regulated by lysine succinylation. The modified proteins were distributed in multiple subcellular compartments and were involved in a wide variety of biological processes, such as photosynthesis and the Calvin-Benson cycle. CONCLUSION: Lysine-succinylated proteins may play key regulatory roles in metabolism, primarily in photosynthesis and oxidative phosphorylation, as well as in many other cellular processes. In addition to the large number of succinylated proteins associated with photosynthesis and oxidative phosphorylation, some proteins associated with the TCA cycle are succinylated. Our study can serve as a reference for further proteomics studies of the downstream effects of succinylation on the physiology and biochemistry of paper mulberry.


Asunto(s)
Broussonetia , Morus , Broussonetia/metabolismo , China , Lisina/metabolismo , Procesamiento Proteico-Postraduccional , Proteómica , Ácido Succínico
20.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33808323

RESUMEN

Epithelial-mesenchymal transition (EMT) is generally observed in normal embryogenesis and wound healing. However, this process can occur in cancer cells and lead to metastasis. The contribution of EMT in both development and pathology has been studied widely. This transition requires the up- and down-regulation of specific proteins, both of which are regulated by EMT-inducing transcription factors (EMT-TFs), mainly represented by the families of Snail, Twist, and ZEB proteins. This review highlights the roles of key EMT-TFs and their post-translational regulation in cancer metastasis.


Asunto(s)
Transición Epitelial-Mesenquimal/fisiología , Metástasis de la Neoplasia/genética , Factores de Transcripción/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metástasis de la Neoplasia/patología , Neoplasias/genética , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/fisiología , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción/genética , Factores de Transcripción Twist/metabolismo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo
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