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Research Square 2021年

作者： Falzone, Maria E. Feng, Zhang Alvarenga, Omar E. Pang, Yangang Lee, ByoungCheol Cheng, Xiaolu Fortea, Eva Scheuring, Simon Accardi, Alessio Department of Anesthesiology Weill Cornell Medical College United States Department of Biochemistry Weill Cornell Medical College United States Physiology Biophysics and Systems Biology Graduate Program Weill Cornell Medical College United States Department of Physiology and Biophysics Weill Cornell Medical College United States

TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. It was proposed that lipid headgroups move between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryoEM structure of the Ca2+-bound afTMEM16 scramblase in nanodiscs showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not entail specific protein-lipid interactions with the extracellular vestibule. Further, we find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes despite an open pathway. Our results show how afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove. © 2021, CC BY.

关键词： Lipids

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Enhanced IGF-IIRα Expression Exacerbates Lipopolysaccharide-Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

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Environmental Toxicology 2024年第11期39卷 5173-5186页

作者： Boonha, Khwanchit Kuo, Wei-Wen Tsai, Bruce Chi-Kang Hsieh, Dennis Jine-Yuan Lin, Kuan-Ho Lu, Shang-Yeh Kuo, Chia-Hua Yang, Liang-Yo Huang, Chih-Yang Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Cardiovascular and Mitochondrial Related Disease Research Center Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan Faculty of Tropical Medicine Mahidol University Bangkok Thailand Department of Biological Science and Technology College of Life Sciences China Medical University Taichung Taiwan PhD Program for Biotechnology Industry China Medical University Taichung Taiwan School of Pharmacy China Medical University Taichung Taiwan Department of Medical Laboratory and Biotechnology Chung Shan Medical University Taichung Taiwan Clinical Laboratory Chung Shan Medical University Hospital Taichung Taiwan Department of Emergency Medicine China Medical University Hospital Taichung Taiwan College of Medicine China Medical University Taichung Taiwan Division of Cardiovascular Medicine Department of Internal Medicine China Medical University Hospital Taichung Taiwan Laboratory of Exercise Biochemistry University of Taipei Taipei Taiwan Institute of Sports Sciences University of Taipei Taipei Taiwan Department of Kinesiology and Health Science College of William and Mary WilliamsburgVA United States School of Physical Education and Sports Science Soochow University Suzhou China Department of Physiology School of Medicine College of Medicine China Medical University Taichung Taiwan Laboratory for Neural Repair China Medical University Hospital Taichung Taiwan Department of Medical Research China Medical University Hospital China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology Asia University Taichung Taiwan Center of General Education Buddhist Tzu Chi Medical Foundation Tzu Chi University of Science and Technology Hualien Taiwan

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function. © 2024 Wiley Periodicals LLC.

关键词： Heart

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Photoswitchable Serotonins for Optical Control of the 5-HT2AReceptor**

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Angewandte Chemie 2022年第18期134卷

作者： Johannes Morstein Giovanna Romano Belinda E. Hetzler Ambrose Plante Caleb Haake Joshua Levitz Dirk Trauner Department of Chemistry New York University New York NY 10003 USA Physiology Biophysics and Systems Biology Graduate Program and Department of Biochemistry Weill Cornell Medicine New York NY 10065 USA

Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT 2A R agonism, with greater activity in the cis -form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HT s provide rapid, reversible, and repeatable optical control following conjugation to SNAP-tagged 5-HT 2A R. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.

关键词： GPCR Photopharmacology Photoswitch Serotonin SNAP Tag

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BPS2025 - Metabolic generation and regulation of mitochondrial outer membrane potential by VDAC

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Biophysical Journal 2025年第3期124卷 449a-449a页

作者： Megha Rajendran Kaitlin Abrantes Bethel G. Beyene William M. Rosencrans Wendy Fitzgerald Sergey M. Bezrukov Tatiana K. Rostovtseva Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA Physiology Biophysics and Systems Biology Graduate Program Weill Cornell Medicine New York NY USA Department of Chemistry and Biochemistry University of Maryland Baltimore County Baltimore MD USA Division of Biology and Biological Engineering California Institute of Technology Pasadena CA USA

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Asymmetric opening of HIV-1 Env bound to CD4 and a coreceptor-mimicking antibody (vol 26, pg 1127, 2019)

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NATURE STRUCTURAL & MOLECULAR BIOLOGY 2020年第2期27卷 222-222页

作者： Yang, Zhi Wang, Haoqing Liu, Albert Z. Gristick, Harry B. Bjorkman, Pamela J. Division of Biology and Biological Engineering California Institute of Technology Pasadena USA Molecular and Cellular Physiology Stanford University Stanford USA Biochemistry Cellular and Molecular Biology Graduate Program Johns Hopkins University School of Medicine Baltimore USA

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Titania Nanosheets Generates Peroxynitrite for S-Nitrosylation and Enhanced p53 Function in Lung Cancer Cells

Research Square

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Research Square 2021年

作者： Soonnarong, Rapeepun Tungsukruthai, Sucharat Nutho, Bodee Rungrotmongkol, Thanyada Vinayanuwattikun, Chanida Maluangnont, Tosapol Chanvorachote, Pithi Interdisciplinary Program of Pharmacology Graduate School Chulalongkorn University Bangkok Thailand Cell-based Drug and Health Products Development Research Unit Chulalongkorn University Bangkok Thailand Departments of Pharmacology and Physiology Faculty of Pharmaceutical Sciences Bangkok Thailand Department of Pharmacology Faculty of Science Mahidol University Bangkok Thailand Biocatalyst and Environmental Biotechnology Reseach Unit Department of Biochemistry Faculty of Science Chulalongkorn University Bangkok Thailand Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University Bangkok Thailand Division of Medical Oncology Department of Medicine Chulalongkorn University Bangkok Thailand College of Materials Innovation and Technology King Mongkut’s Institute of Technology Ladkrabang Bangkok Thailand

Background: Metal oxide nanomaterials are increasingly being exploited in cancer therapy thanks to their unique properties, which can enhance the efficacy of current cancer therapies. However, the nanotoxicity and mechanism of Ti0.8O2 nanosheets for specific site-targeting strategies in NSCLC have not yet been investigated. Methods: The effects of Ti0.8O2 nanosheets on cytotoxicity in NSCLC cells and normal cells were examined. The apoptosis characteristics, including condensed and fragmented nuclei, as assessed by positive staining with annexin V. The cellular uptake of the nanosheets and the induction of stress fiber were assessed via transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses, respectively. We also evaluated the expression of protein in death mechanism to identify the molecular mechanisms behind the toxicity of these cells. We investigated the relationship between S-nitrosylation and the increase in p53 stability by molecular dynamics. Results: Ti0.8O2 nanosheets caused cytotoxicity in several lung cancer cells, but not in normal cells. The nanosheets could enter lung cancer cells and exert an apoptosis induction. Results for protein analysis further indicated the activation of p53, increased Bax, decreased Bcl-2 and Mcl-1, and activation of caspase-3. The nanosheets also exhibited a substantial apoptosis effect in drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than that of cisplatin and etoposide. In terms of their mechanism of action, we found that the mode of apoptosis induction was through the generation of cellular ONOO− mediated the S-nitrosylation of p53 at C182. Molecular dynamics analysis further showed that the S-nitrosylation of one C182 stabilized the p53 dimer. Consequently, this nitrosylation of the protein led to an upregulation of p53 through its stabilization. Conclusions: Taking all the evidence together, we provided info

关键词： Molecular dynamics

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Vitamin D3 as adjuvant in the treatment of type 2 diabetes mellitus: modulation of genomic and biochemical instability (vol 34, pg 135, 2019)

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MUTAGENESIS 2019年第2期34卷 215-215页

作者： Fagundes, Gabriela Elibio Macan, Tamires Pavei Rohr, Paula Damiani, Adriani Paganini da Rocha, Franciani Rodrigues Pereira, Maiara Longaretti, Luiza Martins Vilela, Thais Cereser Ceretta, Luciane Bisognin Mendes, Carolini Silveira, Paulo Cesar Lock Teixeira, Joao Paulo Fernandes de Andrade, Vanessa Moraes Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Laboratory of Exercise Biochemistry and Physiology Department of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Translational Biomedicine Laboratory Graduate Programme of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Graduate Program in Public Health University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Laboratory of Exercise Biochemistry and Physiology Department of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Laboratory of Exercise Biochemistry and Physiology Department of Health Sciences University of Southern Santa Catarina UNESC Criciúma Santa Catarina Brazil Department of Environmental Health National Institute of Health Dr. Ricardo Jorge Porto Portugal

Type 2 diabetes mellitus has undergone a worldwide growth in incidence in the world and has now acquired epidemic status. There is a strong link between type 2 diabetes and vitamin D deficiency. Because vitamin D has beneficial effects on glucose homeostasis, the aim of this study was to evaluate the influence of vitamin D3 supplementation on the modulation of glycaemic control and other metabolic effects, as well as modulation of genomic instability in patients with type 2 diabetes. We evaluated 75 patients with type 2 diabetes, registered in the Integrated Clinics of the University of Southern Santa Catarina. Participants received 4000 IU of vitamin D3 (25(OH)D) supplementation daily for 8 weeks. Blood samples were collected at the beginning and at the end of the supplementation, and 4 weeks after the end of supplementation. The glycidic and lipid profiles [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein and triglycerides], oxidative stress, DNA damage and 25(OH)D levels were evaluated. Vitamin D3 supplementation for 8 weeks showed enough to significantly increase blood levels of 25(OH)D. A significant difference in lipid profile was observed only in non-HDL cholesterol. Significant changes were observed in glucose homeostasis (fasting glucose and serum insulin) and, in addition, a reduction in the parameters of oxidative stress and DNA damage. There was a significant reduction in the values of 25(OH)D 4 weeks after the end of the supplementation, but levels still remained above baseline. Use of vitamin D supplementation can be an ally in the health modulation of patients with type 2 diabetes mellitus.

关键词： cholecalciferol diabetes mellitus dna damage epidemics fasting blood glucose measurement fasting lipid profile genome genomic instability glucose control glucose homeostasis high density lipoproteins immunologic adjuvants insulin low-density lipoproteins non-hdl cholesterol oxidative stress pharmaceutical adjuvants total cholesterol type 2 vitamin d vitamin d deficiency

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The phosphatase activity of the PPP2R5D-PP2A holoenzyme modulates liprin-α1 liquid-liquid phase separation

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The Journal of biological chemistry 2025年 110349页

作者： Abigail Mayer Rita Derua Elijah Spahn Iris Verbinnen Yang Zhang Michelle Guzman Mark R Swingle Brian E Wadzinski Richard Honkanen Veerle Janssens Houhui Xia Neuroscience Graduate Program Department of Neuroscience University of Rochester Medical Center Rochester NY 14642. Laboratory of Protein Phosphorylation & Proteomics Department of Cellular & Molecular Medicine KU Leuven Belgium Sybioma KU Leuven Belgium. Department of Pharmacology and Physiology University of Rochester Medical Center Rochester NY 14642. KU Leuven Institute for Rare Diseases (Leuven.IRD) Belgium. Department of Pharmacology Vanderbilt University Nashville TN 37232. Department of Biochemistry and Molecular Biology University of South Alabama Mobile AL 36688. KU Leuven Institute for Rare Diseases (Leuven.IRD) Belgium. Electronic address: veerle.janssens@kuleuven.be. Neuroscience Graduate Program Department of Neuroscience University of Rochester Medical Center Rochester NY 14642 Department of Pharmacology and Physiology University of Rochester Medical Center Rochester NY 14642. Electronic address: Houhui_xia@urmc.rochester.edu.

Liprin-α1 is a widely expressed scaffolding protein known to regulate cellular processes such as cell motility and synaptic transmission through assembly of localized higher-order molecular complexes. However, the dynamic regulation of these complexes remains poorly understood. Liquid-liquid phase separation (LLPS) is a process that concentrates proteins into cellular nanodomains, facilitating efficient spatiotemporal signaling. Whether liprin-α1 undergoes regulated LLPS remains unclear. MS-based interactomics identified PPP2R5D, the regulatory B56δ subunit of PP2A, as a liprin-α1 interaction partner via a canonical short linear motif (SLiM) in its N-terminal dimerization domain. Mutation of SLiM4 nearly abolished liprin-α1 interaction with PP2A holoenzyme and resulted in a significant increase in GFP-liprin-α1 LLPS in HEK293 cells. Consistently, GFP-liprin-α1 exhibited increased droplet formation in PPP2R5D knockout HEK293 cells. Phospho-analysis of liprin-α1 SLiM4 mutant via MS revealed increased phosphorylation of multiple Ser/Thr sites, including S763, as validated by a novel phospho-specific antibody. A liprin-α1 S763E phospho-mimetic mutant appeared sufficient to drive LLPS. Expression of the PPP2R5D missense variant E420K, recurrently found in Houge-Janssens Syndrome Type 1 compromised suppression of liprin-α1 LLPS, correlating with increased liprin-α1 S763 phosphorylation. Mechanistically, a liprin-α1 E942A mutant unable to bind liprin-β1 underwent increased LLPS, despite preserved PPP2R5D holoenzyme binding. Furthermore, liprin-α1/β1 heterodimerization significantly decreased under conditions where liprin-α1 LLPS was promoted, i.e. upon SLiM4 or S763E mutation in wild type cells, or in PPP2R5D knockout and PPP2R5D E420K knock-in cells. Our findings identify liprin-β1 and PPP2R5D-PP2A as potent inhibitors of liprin-α1 LLPS, with PP2A contributing to liprin-α1/β1 heterodimerization via phosphorylation of at least liprin-α1 S763.

关键词： Houge-Janssens syndrome (HSJ) fluorescence recovery after photobleaching (FRAP) intrinsically disordered protein domain liprin-α1 liprin-β1 mass spectrometry (MS) phase separation phosphorylation protein phosphatase 2A (PP2A)

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SPICE, A Dataset of Drug-like Molecules and Peptides for Training Machine Learning Potentials

arXiv

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arXiv 2022年

作者： Eastman, Peter Behara, Pavan Kumar Dotson, David L. Galvelis, Raimondas Herr, John E. Horton, Josh T. Mao, Yuezhi Chodera, John D. Pritchard, Benjamin P. Wang, Yuanqing De Fabritiis, Gianni Markland, Thomas E. Department of Chemistry Stanford University StanfordCA94305 United States Department of Pharmaceutical Sciences University of California IrvineCA92697 United States The Open Force Field Initiative Open Molecular Software Foundation DavisCA95616 United States Acellera Labs Doctor Trueta 183 Barcelona08005 Spain Department of Chemistry and Biochemistry University of Notre Dame Notre DameIN46556 United States School of Natural and Environmental Sciences Newcastle University Newcastle upon TyneNE1 7RU United Kingdom Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Molecular Sciences Software Institute Virginia Polytechnic Institute State University BlacksburgVA24060 United States Carrer Dr. Aiguader 88 Barcelona08003 Spain ICREA Passeig Lluis Companys 23 Barcelona08010 Spain Graduate Program in Physiology Biophysics and Systems Biology Weill Cornell Graduate School of Medical Sciences New YorkNY10065 United States

Machine learning potentials are an important tool for molecular simulation, but their development is held back by a shortage of high quality datasets to train them on. We describe the SPICE dataset, a new quantum chemistry dataset for training potentials relevant to simulating drug-like small molecules interacting with proteins. It contains over 1.1 million conformations for a diverse set of small molecules, dimers, dipeptides, and solvated amino acids. It includes 15 elements, charged and uncharged molecules, and a wide range of covalent and non-covalent interactions. It provides both forces and energies calculated at the ωB97M-D3(BJ)/def2-TZVPPD level of theory, along with other useful quantities such as multipole moments and bond orders. We train a set of machine learning potentials on it and demonstrate that they can achieve chemical accuracy across a broad region of chemical space. It can serve as a valuable resource for the creation of transferable, ready to use potential functions for use in molecular simulations. Copyright © 2022, The Authors. All rights reserved.

关键词： Quantum chemistry

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Corrigendum to "Analysis of the mechanisms of action of isopentyl caffeate against Leishmania". Biochimie 189 (2021) 158-167

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Biochimie 2022年 201卷 213-214页

作者： Simone S C Oliveira Carine S F Marques Damião P de Sousa Luciana N Andrade Alini T Fricks Sona Jain Marta H Branquinha Eliana B Souto André L S Santos Patrícia Severino Institute of Microbiology Paulo de Góes Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil. University of Tiradentes (Unit) Biotechnological Postgraduate Program Aracaju Sergipe Brazil Institute of Technology and Research (ITP) Nanomedicine and Nanotechnology Laboratory (LNMed) Aracaju Sergipe Brazil. Department of Physiology Federal University Paraíba (UFPB) João Pessoa Paraíba Brazil. Department of Medicine Federal University of Sergipe Lagarto Sergipe Brazil. Faculty of Pharmacy University of Coimbra Azinhaga de Santa Comba 3000-548 Coimbra Portugal CEB - Centre of Biological Engineering University of Minho Campus de Gualtar 4710-057 Braga Portugal. Electronic address: ebsouto@ff.uc.pt. Institute of Microbiology Paulo de Góes Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil Graduate Program in Biochemistry Institute of Chemistry Federal University of Rio de Janeiro Rio de Janeiro Brazil. Electronic address: andre@micro.ufrj.br.

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