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Biochemistry & Molecular Biology
Terry C. Yin et al.
Summary: Energy homeostasis is a complex system involving multiple hormones, neuropeptides, and receptors. Prokineticins (PK1 and PK2) are agonists to two G protein-coupled receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2), which decrease food intake when injected in rodents. This study investigates the relative contribution of PKR1 and PKR2 to the anorexigenic effect of PK2, as well as their site of action in the brain, and the role of MRAP2 in modulating PK2 activity. The results demonstrate that the anorexigenic effect of PK2 is mediated by PKR2 in the amygdala and that MRAP2 can alter PK2 activity in PKR2 neurons.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
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Biochemistry & Molecular Biology
Martin Golkowski et al.
Summary: Dynamic changes in protein-protein interaction networks have significant implications for cellular functions and human diseases. Our study presents a quantitative mass spectrometry-based chemoproteomic method called kinobead competition and correlation analysis (kiCCA) that enables rapid and extensive profiling of kinase interactomes. Using kiCCA, we identified context-dependent kinase interactome changes in diverse cancer lines and discovered potential drug targets. Our findings highlight the importance of studying kinase interactome dynamics for understanding cellular signaling in health and disease.
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Biochemistry & Molecular Biology
Keith J. Kelleher et al.
Summary: The Illuminating the Druggable Genome (IDG) project aims to improve our understanding of understudied proteins and our ability to study them in the context of disease biology by perturbing them with small molecules, biologics, or other therapeutic modalities. The two main products of the IDG effort are the Target Central Resource Database (TCRD), which curates and aggregates information, and Pharos, a web interface for extracting and visualizing data from TCRD. The latest versions of TCRD and Pharos provide visualization and analysis tools that help reveal higher-level patterns in the underlying data.
NUCLEIC ACIDS RESEARCH
(2023)
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Biochemistry & Molecular Biology
Sara Danielli et al.
Summary: CALHM6, a membrane ion channel, promotes cell-cell crosstalk at neuronal synapses via ATP release and is highly expressed in immune cells. It has been linked to NK cell anti-tumor activity, but its mechanism of action and broader functions in the immune system remain unclear.
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Biochemistry & Molecular Biology
Zhuo Xing et al.
Summary: Understanding the mechanisms underlying trisomy and its consequences is important for treating the clinical manifestations associated with this condition. Through the use of mouse models, researchers have found that the phenotypic effects of trisomy can be independent of gene dosage effects. This model system provides a deeper understanding of trisomies and their effects, allowing for new insights into other human diseases.
HUMAN MOLECULAR GENETICS
(2023)
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Cell Biology
Abraham Nguyen et al.
Summary: TTBK2 is a key regulator of primary cilia assembly and stability. It plays a role in maintaining the stability of the ciliary axoneme and regulating the composition of centriolar satellites and basal body pools.
MOLECULAR BIOLOGY OF THE CELL
(2023)
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Urology & Nephrology
Ji Young Kim et al.
KIDNEY INTERNATIONAL
(2023)
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Chemistry, Medicinal
Ann M. Decker et al.
Summary: This study synthesized and characterized the first GPR88 radio-ligand, [3H]RTI-33, derived from a synthetic agonist RTI-13951-33. [3H]RTI-33 showed specific and saturable binding (KD of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells, and a competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
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Biochemistry & Molecular Biology
Chien-Ting Wu et al.
Summary: Using primary nasal epithelial organoid cultures, researchers discovered that SARS-CoV-2 attaches to motile cilia through the ACE2 receptor. The virus then traverses the mucus layer using these cilia as tracks to access the cell body. Depletion of cilia inhibits infection not only by SARS-CoV-2 but also other respiratory viruses. Furthermore, the study found that SARS-CoV-2 progeny attach to airway microvilli and trigger the formation of extended and branched microvilli, facilitating viral egress from the microvilli back into the mucus layer. This supports the model of virus dispersion throughout the airway tissue via mucociliary transport. Remarkably, the Omicron variants exhibit higher affinity to motile cilia and demonstrate accelerated viral entry. The findings highlight the critical role of motile cilia, microvilli, and mucociliary-dependent mucus flow in efficient virus replication in nasal epithelia.
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Biochemistry & Molecular Biology
Austin M. Reilly et al.
Summary: This study characterizes the metabolic phenotypes of adult GIRKO mice switched to a high-fat diet, revealing important gene-diet interactions contributing to the progression of diabetes. The findings suggest that the development of insulin resistance, dyslipidemia, and gut inflammation are key factors in driving the onset and progression of diabetes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
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Dermatology
E. Lerner
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(2022)
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Immunology
Shrestha Ghosh et al.
Summary: The study reveals that the atypical kinase RIOK2 acts as a transcription factor governing human hematopoietic differentiation by enhancing certain gene expressions and suppressing others. This finding sheds light on the regulatory network of blood cell development and potential therapeutic targets for hematologic disorders.
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Computer Science, Interdisciplinary Applications
Nickolas Fularczyk et al.
Summary: This paper introduces a new quantitative framework based on supervised learning to investigate structural alterations in the neuronal cytoskeleton of schizophrenia patients. By using Support Vector Machines or selected Artificial Neural Networks, it is possible to predict schizophrenia and healthy control cells reliably, and discover differential regulation of two cytoskeleton components in schizophrenia and healthy control cells.
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Biochemistry & Molecular Biology
Mihaly Varadi et al.
Summary: AlphaFold DB is an openly accessible database with high-accuracy protein-structure predictions, powered by DeepMind's AlphaFold v2.0. It provides programmatic access to a vast number of predicted structures and is expanding to cover more sequences.
NUCLEIC ACIDS RESEARCH
(2022)
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Biochemistry & Molecular Biology
Marc Gillespie et al.
Summary: The Reactome Knowledgebase, a core resource of Elixir, provides manually curated molecular details of human biological processes, serving as a digital archive and tool for discovering functional relationships. Recent work has expanded annotations of signaling processes, drugs targeting them, infections by coronaviruses, and better analysis tools for high-throughput data and placement of unstudied proteins.
NUCLEIC ACIDS RESEARCH
(2022)
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Multidisciplinary Sciences
Bertrand Simon et al.
Summary: TLK2 selectively targets ASF1 by mimicking its client protein histone H3, promoting nucleosome assembly. This selectivity is achieved through recognition of phosphorylation site motifs in ASF1 by the catalytic domain of TLK2 and interaction between a short sequence at the N-terminus of TLK2 and the N-terminal domain of ASF1.
NATURE COMMUNICATIONS
(2022)
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Cell Biology
Shijun Yan et al.
Summary: The orphan G protein-coupled receptor Gpr17 inhibits the secretion of glucagon-like peptide-1 (GLP-1) in intestinal enteroendocrine cells. Genetic ablation or agonistic action of Gpr17 can increase the secretion of GLP-1.
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Chemistry, Medicinal
Thuy Nguyen et al.
Summary: This study reveals the important structural regions for NPBWR1 agonism and successfully develops stable and potent peptidomimetic agonists targeting NPBWR1.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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Chemistry, Medicinal
David H. Drewry et al.
Summary: The pyrimidine core has been widely used in constructing kinase inhibitors, and the strategy of utilizing nonexemplified aminopyrimidines with side chains from annotated inhibitors has provided useful inhibitors for understudied kinases. By mixing and matching side chains from parent compounds and modifying the 5-position of the pyrimidine core, improved kinome-wide selectivity was achieved. Important lead compounds for understudied kinases such as DRAK1, BMP2K, and MARK3/4 were also identified through this approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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Biochemistry & Molecular Biology
Wenjing Xu et al.
Summary: This study identified four orphan GPCRs expressed at high levels in lymphatic endothelial cells. Using genetic engineering approaches in zebrafish and mice, the function of one of these receptors, GPRC5B, in lymphatic development was characterized. Expression of GPRC5B was found to be required for cell proliferation and viability in human primary LECs. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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Biochemistry & Molecular Biology
Stefanie Jehle et al.
Summary: Protein kinases play a critical role in cellular signaling pathways and their dysregulation can lead to various diseases. A human kinase array was developed to assess kinase activity in yeast, allowing for the study of protein-protein interactions and other related investigations.
MOLECULAR SYSTEMS BIOLOGY
(2022)
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Multidisciplinary Sciences
Annette Klomp et al.
Summary: Voltage-gated Ca2+ channels play a critical role in the development and function of the nervous system. Mutations in the CACNA2D4 gene, which encodes the alpha(2)delta-4 auxiliary subunit of these channels, are associated with neuropsychiatric and neurodevelopmental disorders. This study investigates the behavioral phenotypes of alpha(2)delta-4 knockout mice and reveals unexpected roles of alpha(2)delta-4 in sensorimotor gating and motor function.
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Multidisciplinary Sciences
Serap Erdogmus et al.
Summary: The regulatory beta subunit of voltage-gated calcium channels regulates T cell function despite no evidence that these channels were functional within T cells during activation.
NATURE COMMUNICATIONS
(2022)
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Multidisciplinary Sciences
Youwen Zhuang et al.
Summary: The study presents cryo-EM structures of formylpeptide receptors FPR1 and FPR2 bound to different agonists and Gi protein, providing insights into the recognition of formylpeptides and synthetic agonists by FPRs and their activation mechanism. This research has significant implications for the rational design of drugs targeting FPRs.
NATURE COMMUNICATIONS
(2022)
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Endocrinology & Metabolism
Hyeon-Young Min et al.
Summary: The overexpression of lactate receptor HCAR1 in interscapular brown adipose tissue (BAT) of male DIO mice promotes glucose uptake, reduces lipolysis, prevents weight gain, improves glucose tolerance and insulin sensitivity. Activation of HCAR1 in BAT restores body weight and metabolic health in obese individuals, suggesting a potential therapeutic target for controlling obesity and glucose metabolism.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2022)
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Neurosciences
Joshua X. Yee et al.
Summary: The researchers used cell-type-specific viral-mediated CRISPR/Cas9 mutagenesis to target the potassium channel auxiliary subunit Kvli2 in dopamine neurons in mice, and found that the absence of Kvli2 altered action potential properties and reduced surface expression of pore-forming subunits. These findings highlight the importance of Kv1 currents in dopamine neuron firing and demonstrate a role for Kvli2 subunits in regulating ion channel properties.
JOURNAL OF NEUROPHYSIOLOGY
(2022)
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Chemistry, Multidisciplinary
Kaavian Shariati et al.
Summary: Researchers have developed an improved fluorescent biosensor that can simultaneously measure chloride ions and pH in the endoplasmic reticulum (ER), which is useful for detecting chloride concentration in environments with challenging protein folding.
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Cell Biology
Melanie Rivera et al.
Summary: This study investigated the impact of Rac1 on critical steps in metastasis through experimental and computational modeling. It identified cell adhesion, rapid intravasation, and survival in the blood as parameters most critically dependent on Rac1 in the ovarian metastatic cascade.
MOLECULAR BIOLOGY OF THE CELL
(2022)
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Biochemistry & Molecular Biology
John T. Happ et al.
Summary: This study reveals that SMO uses a pseudosubstrate sequence to block the active site of PKA, extinguishing its enzymatic activity and releasing GLI for signal transduction. The interference with SMO-PKA interactions prevents Hh signal transduction.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
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Virology
Thomas C. Bisom et al.
Summary: The RIOK3 protein and its spliced isoform RIOK3 X2 play distinct roles in different innate immune pathways during Rift Valley fever virus infection.
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Multidisciplinary Sciences
Devasena Ponnalagu et al.
Summary: Mitochondrial-associated membranes (MAMs) play a crucial role in modulating cellular response to myocardial ischemia-reperfusion (IR) injury. The chloride intracellular channel protein (CLIC4), found in MAMs of cardiomyocytes, is involved in regulating ER and mitochondrial calcium homeostasis. Loss of CLIC4 increases myocardial infarction and impairs cardiac function after IR injury. CLIC4 deficiency leads to increased apoptosis and mitochondrial dysfunction in cardiomyocytes.
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Biology
Yuna Choi et al.
Life Science Alliance
(2022)
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Mathematical & Computational Biology
Dhouha Grissa et al.
Summary: The DISEASES database has been significantly updated to provide a more comprehensive overview of disease-gene associations, with a major increase in the number of associations from various sources. The increase in text-mined associations, primarily due to the inclusion of full-text articles in the corpus and improvements in entity recognition dictionaries, is particularly remarkable. Additionally, the integration of a new GWAS database has substantially contributed to the increase in GWAS-derived disease-gene associations.
DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION
(2022)
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Biochemistry & Molecular Biology
Daphne E. Eagleman et al.
Summary: The study explored the regulation of ER stress response by Nedd4-2 in neuronal cells, revealing a novel mechanism involving ribosomal protein expression and ubiquitination. The findings suggest a potential role of Nedd4-2 in translational control under ER stress, providing insights into neurological diseases associated with dysregulated ER stress response or Nedd4-2 function.
JOURNAL OF NEUROCHEMISTRY
(2021)
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Biochemistry & Molecular Biology
Matthew E. Berginski et al.
Summary: Kinases play crucial roles in cell signaling pathways, with known dysfunctions being linked to various pathologies. However, the functions of nearly one-third of kinases remain largely unknown. The Dark Kinase Knowledgebase (DKK) aims to provide data and reagents for these understudied kinases, supporting the broader research community in exploring potentially high-impact druggable targets.
NUCLEIC ACIDS RESEARCH
(2021)
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Biochemistry & Molecular Biology
Taran Khanam et al.
Summary: Mutations in the gene encoding the CDKL5 kinase are common genetic causes of childhood epilepsy and CDKL5 deficiency disorder. CDKL5 is recruited to sites of DNA damage in actively transcribed regions of the nucleus and is involved in phosphorylating transcriptional regulators like ELOA. Additionally, CDKL5 kinase activity is essential for the transcriptional silencing of genes induced by DNA double-strand breaks, revealing its role as a DNA damage-sensing, PAR-controlled transcriptional modulator.
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Biochemical Research Methods
Joseph T. Vecchi et al.
Summary: NeuriteNet is a Convolutional Neural Network sorting model that effectively categorizes neuronal images into different groups and highlights distinguishing features using a saliency map overlay.
JOURNAL OF NEUROSCIENCE METHODS
(2021)
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Virology
Katherine E. Havranek et al.
Summary: Recent studies have shown that during RVFV infection, the host splicing landscape changes, with the selective splicing of RIOK3 playing a crucial role in the interferon signaling pathway.
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Multidisciplinary Sciences
Heng Liu et al.
Summary: Ghrelin is a central orexigenic peptide hormone that activates the GHSR to stimulate food intake and growth hormone secretion. Synthetic agonists of GHSR are being evaluated for disorders related to appetite and growth hormone dysregulation. The high-resolution cryo-EM structures provide insights into the molecular basis of ghrelin and ibutamoren binding for drug design.
NATURE COMMUNICATIONS
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Oncology
Siddesh Southekal et al.
Summary: This study analyzed the DNA methylation and gene expression patterns of the human kinome in 32 cancers, revealing significant differences in methylation levels between tumor and normal samples from the same tissue. The meQTL analysis showed a highly significant and mostly negative correlation between kinase gene expression and methylated probes within 1.5 kb from the transcription start site (TSS). Additionally, several understudied kinases were identified with a significant impact on patient survival, highlighting the potential of kinases as prognostic and diagnostic markers in cancer.
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Pharmacology & Pharmacy
Jonathan Pascale et al.
Summary: This study investigates the interaction between GPR75 receptor and its ligand 20-HETE, revealing that 20-HETE is a high-affinity ligand for GPR75, while CCL5 acts as a low-affinity negative regulator of GPR75.
BRITISH JOURNAL OF PHARMACOLOGY
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Immunology
Mahesh Raundhal et al.
Summary: The study reveals that haplosufficiency of the serine-threonine kinase RIOK2 leads to decreased erythroid precursor frequency and subsequent anemia, with IL-22 playing a crucial role in affecting erythroid precursors. Blocking IL-22 signaling alleviates anemia, suggesting a potential therapeutic target for stress-induced anemias. The findings also suggest that immune dysregulation is involved in the pathogenesis of myelodysplastic syndromes.
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Oncology
Margarite D. Matossian et al.
Summary: NEK5 plays a role in breast cancer cell morphology and migration, but does not affect tumor growth kinetics. Its overexpression or knockdown can respectively promote or suppress metastatic potential in a cell type-specific manner. NEK5 affects cell seeding capabilities but not metastatic colonization or proliferation in vivo.
BREAST CANCER RESEARCH AND TREATMENT
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Md Toufiqur Rahman et al.
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John Jumper et al.
Summary: Proteins are essential for life, and accurate prediction of their structures is a crucial research problem. Current experimental methods are time-consuming, highlighting the need for accurate computational approaches to address the gap in structural coverage. Despite recent progress, existing methods fall short of atomic accuracy in protein structure prediction.
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Can Cao et al.
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