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716 results on '"Velázquez-Campoy, Adrián"'

10. Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid–liquid phase separation

Author

González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á., Elena-Real, Carlos A., Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P., Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M., Salvatella, Xavier, Valpuesta, José M., Hermoso, Juan A., De la Rosa, Miguel A., and Díaz-Moreno, Irene

Published
2022
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11. Phosphorylation of cytochrome c at tyrosine 48 finely regulates its binding to the histone chaperone SET/TAF‐Iβ in the nucleus.

Author

Tamargo‐Azpilicueta, Joaquin, Casado‐Combreras, Miguel Á., Giner‐Arroyo, Rafael L., Velázquez‐Campoy, Adrián, Márquez, Inmaculada, Olloqui‐Sariego, José L., De la Rosa, Miguel A., and Diaz‐Moreno, Irene

Abstract

Post‐translational modifications (PTMs) of proteins are ubiquitous processes present in all life kingdoms, involved in the regulation of protein stability, subcellular location and activity. In this context, cytochrome c (Cc) is an excellent case study to analyze the structural and functional changes induced by PTMS as Cc is a small, moonlighting protein playing different roles in different cell compartments at different cell‐cycle stages. Cc is actually a key component of the mitochondrial electron transport chain (ETC) under homeostatic conditions but is translocated to the cytoplasm and even the nucleus under apoptotic conditions and/or DNA damage. Phosphorylation does specifically alter the Cc redox activity in the mitochondria and the Cc non‐redox interaction with apoptosis‐related targets in the cytoplasm. However, little is known on how phosphorylation alters the interaction of Cc with histone chaperones in the nucleus. Here, we report the effect of Cc Tyr48 phosphorylation by examining the protein interaction with SET/TAF‐Iβ in the nuclear compartment using a combination of molecular dynamics simulations, biophysical and structural approaches such as isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) and in cell proximity ligation assays. From these experiments, we infer that Tyr48 phosphorylation allows a fine‐tuning of the Cc‐mediated inhibition of SET/TAF‐Iβ histone chaperone activity in vitro. Our findings likewise reveal that phosphorylation impacts the nuclear, stress‐responsive functions of Cc, and provide an experimental framework to explore novel aspects of Cc post‐translational regulation in the nucleus. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Thermal Liquid Biopsy: A Promising Tool for the Differential Diagnosis of Pancreatic Cystic Lesions and Malignancy Detection.

Author

Millastre, Judith, Hermoso-Durán, Sonia, Solórzano, María Ortiz de, Fraunhoffer, Nicolas, García-Rayado, Guillermo, Vega, Sonia, Bujanda, Luis, Sostres, Carlos, Lanas, Ángel, Velázquez-Campoy, Adrián, and Abian, Olga

Subjects
TUMOR classification, PREDICTIVE tests, DIFFERENTIAL diagnosis, PREDICTION models, RESEARCH funding, PANCREATIC cysts, EARLY detection of cancer, BODY fluid examination, CANCER patients, TUMOR markers, RETROSPECTIVE studies, DESCRIPTIVE statistics, PANCREAS, PANCREATIC tumors, MEDICAL records, ACQUISITION of data, NEEDLE biopsy, MACHINE learning, ALGORITHMS, SENSITIVITY & specificity (Statistics)
Abstract

Simple Summary: Mucinous epithelial pancreatic cystic lesions (PCLs) are premalignant lesions detectable through imaging techniques; however, distinguishing them from other PCLs with lower malignancy potential is challenging. Current methods like biochemical markers and genomic studies are not always reliable. Thermal liquid biopsy (TLB) is an innovative tool that analyzes the thermal profile of biological samples to detect disease-related alterations. In a retrospective study of 35 intracystic fluid samples obtained via fine needle aspiration, predictive models were developed using machine learning algorithms. Two classification models were created: TLB1, which differentiates mucinous from non-mucinous PCLs, demonstrating 92% sensitivity and 86% negative predictive value, and TLB2, which identifies benign and malignant mucinous lesions, achieving an area under the curve of 1.00. TLB shows promise in improving the differential diagnosis of PCLs and in detecting malignant transformations. Background/Objectives: Mucinous epithelial pancreatic cystic lesions (PCLs) are premalignant lesions readily detectable through imaging techniques such as multidetector computed tomography, magnetic resonance imaging, and endoscopic ultrasound (EUS). However, distinguishing these from other PCLs with lower or no malignant potential, and the early identification of those undergoing malignant transformation, remains a diagnostic challenge. Current methods, including biochemical markers in intracystic fluid (ICF) and genomic studies, offer some assistance but are not always reliable or accessible. Thermal liquid biopsy (TLB) is a novel diagnostic tool that examines the thermal profile (thermogram) of biological samples, reflecting their response to heat and thereby revealing characteristics of their overall composition or disease-induced alterations. Methods: In this retrospective study, a total of 35 ICF samples (49% mucinous) obtained via EUS-FNA (fine needle aspiration) were analyzed using TLB. Thermogram data were utilized to develop predictive models for differential diagnosis between mucinous and non-mucinous PCLs or malignancy detection through machine learning algorithms. Results: Two classification models were developed: TLB1 ("mucinous" vs. "non-mucinous" PCLs) and TLB2 ("benign mucinous" vs. "malignant mucinous" PCLs). The TLB1 model demonstrated a sensitivity of 92% and a negative predictive value of 86%, with an area under the curve (AUC) of 0.79 (0.59–0.99), indicating good discriminative ability between the two groups. The TLB2 model exhibited excellent predictive capability, with an AUC of 1.00. Conclusions: TLB analysis of PCLs is a promising tool that could significantly enhance the differential diagnosis of PCLs, enabling the efficient identification of mucinous lesions and even those undergoing malignant transformation. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Unprecedented pathway of reducing equivalents in a diflavin-linked disulfide oxidoreductase

Author

Buey, Rubén M, Arellano, Juan B, López-Maury, Luis, Galindo-Trigo, Sergio, Velázquez-Campoy, Adrián, Revuelta, José L, de Pereda, José M, Florencio, Francisco J, Schürmann, Peter, Buchanan, Bob B, and Balsera, Monica

Subjects
Amino Acid Sequence, Bacterial Proteins, Binding Sites, Biocatalysis, Cell Membrane, Crystallography, X-Ray, Cyanobacteria, Disulfides, Flavin-Adenine Dinucleotide, Gene Expression, Kinetics, Models, Molecular, Oxidoreductases, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Folding, Protein Interaction Domains and Motifs, Recombinant Proteins, Sequence Alignment, Structural Homology, Protein, Substrate Specificity, Synechocystis, Thioredoxin-Disulfide Reductase, flavoprotein, transfer of reducing equivalents, redox active disulfide, Rossmann fold, sulfhydryl
Abstract

Flavoproteins participate in a wide variety of physiologically relevant processes that typically involve redox reactions. Within this protein superfamily, there exists a group that is able to transfer reducing equivalents from FAD to a redox-active disulfide bridge, which further reduces disulfide bridges in target proteins to regulate their structure and function. We have identified a previously undescribed type of flavin enzyme that is exclusive to oxygenic photosynthetic prokaryotes and that is based on the primary sequence that had been assigned as an NADPH-dependent thioredoxin reductase (NTR). However, our experimental data show that the protein does not transfer reducing equivalents from flavins to disulfides as in NTRs but functions in the opposite direction. High-resolution structures of the protein from Gloeobacter violaceus and Synechocystis sp. PCC6803 obtained by X-ray crystallography showed two juxtaposed FAD molecules per monomer in redox communication with an active disulfide bridge in a variant of the fold adopted by NTRs. We have tentatively named the flavoprotein "DDOR" (diflavin-linked disulfide oxidoreductase) and propose that its activity is linked to a thiol-based transfer of reducing equivalents in bacterial membranes. These findings expand the structural and mechanistic repertoire of flavoenzymes with oxidoreductase activity and pave the way to explore new protein engineering approaches aimed at designing redox-active proteins for diverse biotechnological applications.

Published
2017

25. Novel Drug-like HsrA Inhibitors Exhibit Potent Narrow-Spectrum Antimicrobial Activities against Helicobacter pylori.

Author

Casado, Javier, Olivan-Muro, Irene, Algarate, Sonia, Chueca, Eduardo, Salillas, Sandra, Velázquez-Campoy, Adrián, Piazuelo, Elena, Fillat, María F., Sancho, Javier, Lanas, Ángel, and González, Andrés

Subjects
HELICOBACTER pylori infections, HELICOBACTER pylori, CAMPYLOBACTER jejuni, PROTEIN synthesis, HUMAN microbiota
Abstract

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Phosphorylation at the disordered N-end makes HuR accumulate and dimerize in the cytoplasm.

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Agencia Estatal de Investigación. España, Ministerio de Ciencia e Innovación (MICIN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, Universidad de Sevilla, Ministerio de Educación, Cultura y Deporte (MECD). España, Baños Jaime, Blanca, Corrales Guerrero, Laura, Pérez Mejías, Gonzalo, Rejano Gordillo, Claudia M., Velázquez Campoy, Adrián, Martínez Cruz, Luis Alfonso, Rosa Acosta, Miguel Ángel de la, Díaz Moreno, Irene, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Agencia Estatal de Investigación. España, Ministerio de Ciencia e Innovación (MICIN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, Universidad de Sevilla, Ministerio de Educación, Cultura y Deporte (MECD). España, Baños Jaime, Blanca, Corrales Guerrero, Laura, Pérez Mejías, Gonzalo, Rejano Gordillo, Claudia M., Velázquez Campoy, Adrián, Martínez Cruz, Luis Alfonso, Rosa Acosta, Miguel Ángel de la, and Díaz Moreno, Irene

Abstract

Human antigen R (HuR) is an RNA binding protein mainly involved in maintaining the stability and controlling the translation of mRNAs, critical for immune response, cell survival, proliferation and apoptosis. Although HuR is a nuclear protein, its mRNA translational-related function occurs at the cytoplasm, where the oligomeric form of HuR is more abundant. However, the regulation of nucleo-cytoplasmic transport of HuR and its connection with protein oligomerization remain unclear. In this work, we describe the phosphorylation of Tyr5 as a new hallmark for HuR activation. Our biophysical, structural and computational assays using phosphorylated and phosphomimetic HuR proteins demonstrate that phosphorylation of Tyr5 at the disordered N-end stretch induces global changes on HuR dynamics and conformation, modifying the solvent accessible surface of the HuR nucleo-cytoplasmic shuttling (HNS) sequence and releasing regions implicated in HuR dimerization. These findings explain the preferential cytoplasmic accumulation of phosphorylated HuR in HeLa cells, aiding to comprehend the mechanisms underlying HuR nucleus-cytoplasm shuttling and its later dimerization, both of which are relevant in HuR-related pathogenesis.

Published
2024

31. Supporting information Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

Author

Abian, Olga [0000-0001-5664-1729], Thomson, Timothy M. [0000-0002-4670-9440], Rubio-Martínez, Jaime [jaime.rubio@ub.edu], Peralta-Moreno, María Nuria, Mena, Yago, Ortega-Alarcón, David, Jiménez-Alesanco, Ana, Vega, Sonia, Abian, Olga, Velázquez-Campoy, Adrián, Thomson, Timothy M., Pinto, Marta, Granadino-Roldán, José Manuel, Santos Tomás, Marí, Pérez, Juan J., Rubio-Martínez, Jaime, Abian, Olga [0000-0001-5664-1729], Thomson, Timothy M. [0000-0002-4670-9440], Rubio-Martínez, Jaime [jaime.rubio@ub.edu], Peralta-Moreno, María Nuria, Mena, Yago, Ortega-Alarcón, David, Jiménez-Alesanco, Ana, Vega, Sonia, Abian, Olga, Velázquez-Campoy, Adrián, Thomson, Timothy M., Pinto, Marta, Granadino-Roldán, José Manuel, Santos Tomás, Marí, Pérez, Juan J., and Rubio-Martínez, Jaime

Published
2024

38. Autochthonous Peruvian Natural Plants as Potential SARS-CoV-2 Mpro Main Protease Inhibitors

Author

Generalitat de Catalunya, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Universidad de Barcelona, Fundación hna, Instituto de Investigación Sanitaria Aragón, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Gobierno de Aragón, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Ministerio de Ciencia, Innovación y Universidades (España), Peralta-Moreno, María Nuria [0000-0002-7762-0406], Antón-Muñoz, Vanessa [0009-0000-1640-6177], Ortega-Alarcón, David [0000-0003-1885-4365], Abian, Olga [0000-0001-5664-1729], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Thomson, Timothy M. [0000-0002-4670-9440], Machicado, Claudia [0000-0001-6140-2423], Rubio-Martínez, Jaime [0000-0002-5529-2325], Peralta-Moreno, María Nuria, Antón-Muñoz, Vanessa, Ortega-Alarcón, David, Jiménez-Alesanco, Ana, Vega, Sonia, Abian, Olga, Velázquez-Campoy, Adrián, Thomson, Timothy M., Granadino-Roldán, José Manuel, Machicado, Claudia, Rubio-Martínez, Jaime, Generalitat de Catalunya, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Universidad de Barcelona, Fundación hna, Instituto de Investigación Sanitaria Aragón, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Gobierno de Aragón, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Ministerio de Ciencia, Innovación y Universidades (España), Peralta-Moreno, María Nuria [0000-0002-7762-0406], Antón-Muñoz, Vanessa [0009-0000-1640-6177], Ortega-Alarcón, David [0000-0003-1885-4365], Abian, Olga [0000-0001-5664-1729], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Thomson, Timothy M. [0000-0002-4670-9440], Machicado, Claudia [0000-0001-6140-2423], Rubio-Martínez, Jaime [0000-0002-5529-2325], Peralta-Moreno, María Nuria, Antón-Muñoz, Vanessa, Ortega-Alarcón, David, Jiménez-Alesanco, Ana, Vega, Sonia, Abian, Olga, Velázquez-Campoy, Adrián, Thomson, Timothy M., Granadino-Roldán, José Manuel, Machicado, Claudia, and Rubio-Martínez, Jaime

Abstract

Over 750 million cases of COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been reported since the onset of the global outbreak. The need for effective treatments has spurred intensive research for therapeutic agents based on pharmaceutical repositioning or natural products. In light of prior studies asserting the bioactivity of natural compounds of the autochthonous Peruvian flora, the present study focuses on the identification SARS-CoV-2 Mpro main protease dimer inhibitors. To this end, a target-based virtual screening was performed over a representative set of Peruvian flora-derived natural compounds. The best poses obtained from the ensemble molecular docking process were selected. These structures were subjected to extensive molecular dynamics steps for the computation of binding free energies along the trajectory and evaluation of the stability of the complexes. The compounds exhibiting the best free energy behaviors were selected for in vitro testing, confirming the inhibitory activity of Hyperoside against Mpro, with a Ki value lower than 20 µM, presumably through allosteric modulation.

Published
2023

39. Biological Calorimetry: Old Friend, New Insights

Author

Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Diputación General de Aragón, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Abian, Olga [0000-0001-5664-1729], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Abian, Olga, Vega, Sonia, Velázquez-Campoy, Adrián, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Diputación General de Aragón, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Abian, Olga [0000-0001-5664-1729], Velázquez-Campoy, Adrián [0000-0001-5702-4538], Abian, Olga, Vega, Sonia, and Velázquez-Campoy, Adrián

Abstract

Calorimetry is an old experimental technique (first instrument developed in S. XVIII), but it is broadly used and still provides key information for understanding biological processes at the molecular level, particularly, cooperative phenomena in protein interactions. Here, we review and highlight some key aspects of biological calorimetry. Several biological systems will be described in which calorimetry was instrumental for modeling the behavior of the protein and obtaining further biological insight.

Published
2023

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