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Cellular and Molecular Life Sciences :... Jul 2022Magnesium (Mg) is the most prevalent divalent intracellular cation. As co-factor in many enzymatic reactions, Mg is essential for protein synthesis, energy production,... (Review)
Review
Magnesium (Mg) is the most prevalent divalent intracellular cation. As co-factor in many enzymatic reactions, Mg is essential for protein synthesis, energy production, and DNA stability. Disturbances in intracellular Mg concentrations, therefore, unequivocally result in delayed cell growth and metabolic defects. To maintain physiological Mg levels, all organisms rely on balanced Mg influx and efflux via Mg channels and transporters. This review compares the structure and the function of prokaryotic Mg transporters and their eukaryotic counterparts. In prokaryotes, cellular Mg homeostasis is orchestrated via the CorA, MgtA/B, MgtE, and CorB/C Mg transporters. For CorA, MgtE, and CorB/C, the motifs that form the selectivity pore are conserved during evolution. These findings suggest that CNNM proteins, the vertebrate orthologues of CorB/C, also have Mg transport capacity. Whereas CorA and CorB/C proteins share the gross quaternary structure and functional properties with their respective orthologues, the MgtE channel only shares the selectivity pore with SLC41 Na/Mg transporters. In eukaryotes, TRPM6 and TRPM7 Mg channels provide an additional Mg transport mechanism, consisting of a fusion of channel with a kinase. The unique features these TRP channels allow the integration of hormonal, cellular, and transcriptional regulatory pathways that determine their Mg transport capacity. Our review demonstrates that understanding the structure and function of prokaryotic magnesiotropic proteins aids in our basic understanding of Mg transport.
Topics: Biological Transport; Cations, Divalent; Magnesium; Membrane Transport Proteins; Phosphotransferases
PubMed: 35819535
DOI: 10.1007/s00018-022-04442-8 -
Proceedings of the National Academy of... Aug 2021Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked...
Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5 to PtdIns(4,5) They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.
Topics: CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Cell Survival; Cloning, Molecular; Forkhead Transcription Factors; Gene Expression Regulation, Enzymologic; Humans; Immunosuppression Therapy; Mechanistic Target of Rapamycin Complex 1; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor); Quinazolines; Signal Transduction; T-Lymphocytes, Regulatory; Thiophenes; Ubiquitin-Protein Ligases
PubMed: 34312224
DOI: 10.1073/pnas.2010053118 -
The Plant Cell Apr 2022The nucleotide-binding, leucine-rich receptor (NLR) protein HOPZ-ACTIVATED RESISTANCE 1 (ZAR1), an immune receptor, interacts with HOPZ-ETI-DEFICIENT 1 (ZED1)-related...
The nucleotide-binding, leucine-rich receptor (NLR) protein HOPZ-ACTIVATED RESISTANCE 1 (ZAR1), an immune receptor, interacts with HOPZ-ETI-DEFICIENT 1 (ZED1)-related kinases (ZRKs) and AVRPPHB SUSCEPTIBLE 1-like proteins to form a pentameric resistosome, triggering immune responses. Here, we show that ZAR1 emerged through gene duplication and that ZRKs were derived from the cell surface immune receptors wall-associated protein kinases (WAKs) through the loss of the extracellular domain before the split of eudicots and monocots during the Jurassic period. Many angiosperm ZAR1 orthologs, but not ZAR1 paralogs, are capable of oligomerization in the presence of AtZRKs and triggering cell death, suggesting that the functional ZAR1 resistosome might have originated during the early evolution of angiosperms. Surprisingly, inter-specific pairing of ZAR1 and AtZRKs sometimes results in the formation of a resistosome in the absence of pathogen stimulation, suggesting within-species compatibility between ZAR1 and ZRKs as a result of co-evolution. Numerous concerted losses of ZAR1 and ZRKs occurred in angiosperms, further supporting the ancient co-evolution between ZAR1 and ZRKs. Our findings provide insights into the origin of new plant immune surveillance networks.
Topics: Arabidopsis; Arabidopsis Proteins; Carrier Proteins; NLR Proteins; Phosphotransferases; Plant Immunity
PubMed: 35166827
DOI: 10.1093/plcell/koac053 -
Plant Physiology and Biochemistry : PPB Sep 2021Catharanthus roseous kinase 1L receptors (CrRLK1Ls) are a subfamily of membrane receptors unique to plant cells that perceive internal and external signals, integrate... (Review)
Review
Catharanthus roseous kinase 1L receptors (CrRLK1Ls) are a subfamily of membrane receptors unique to plant cells that perceive internal and external signals, integrate metabolic, physiological, and molecular processes, and regulate plant development. Recent genomic studies have suggested that this receptor subfamily arose during the emergence of terrestrial plants and has since diversified, preserving its essential functions. Participation of some of these CrRLK1Ls in different processes is presented and discussed herein, as well as the increasing number of interactors necessary for their function. At least five different responses have been detected after activating these receptors, such as physiological changes, formation or disassembly of protein complexes, metabolic responses, modification of gene expression, and modulation of phytohormone activity. To date, a common response mechanism for all processes involving CrRLK1Ls has not been described. In this review, the information available on the different functions of CrRLK1Ls was compiled. Additionally, the physiological and/or molecular mechanisms involved in the signaling processes triggered by these receptors are also discussed. In this review, we propose a possible common signaling mechanism for all processes regulated by CrRLK1Ls and pose questions to be answered in the future.
Topics: Catharanthus; Phosphotransferases; Plant Development; Plant Growth Regulators; Plants; Stress, Physiological
PubMed: 34091211
DOI: 10.1016/j.plaphy.2021.05.028 -
Gene May 2023Polypeptides play irreplaceable roles in cell-cell communication by binding to receptor-like kinases. Various types of peptide-receptor-like kinase-mediated signaling... (Review)
Review
Polypeptides play irreplaceable roles in cell-cell communication by binding to receptor-like kinases. Various types of peptide-receptor-like kinase-mediated signaling have been identified in anther development and male-female interactions in flowering plants. Here, we provide a comprehensive summary of the biological functions and signaling pathways of peptides and receptors involved in anther development, self-incompatibility, pollen tube growth and pollen tube guidance.
Topics: Reproduction; Signal Transduction; Cell Communication; Phosphotransferases; Pollen; Peptides; Flowers
PubMed: 36870426
DOI: 10.1016/j.gene.2023.147328 -
Vitamins and Hormones 2022Parathyroid hormone is a central regulator of calcium homeostasis. PTH protects the organism from hypocalcemia through its actions in bone and kidney. Recent physiologic...
Parathyroid hormone is a central regulator of calcium homeostasis. PTH protects the organism from hypocalcemia through its actions in bone and kidney. Recent physiologic studies have revealed key target genes for PTH receptor (PTH1R) signaling in these target organs. However, the complete signal transduction cascade used by PTH1R to accomplish these physiologic actions has remained poorly defined. Here we will review recent studies that have defined an important role for salt inducible kinases downstream of PTH1R in bone, cartilage, and kidney. PTH1R signaling inhibits the activity of salt inducible kinases. Therefore, direct SIK inhibitors represent a promising novel strategy to mimic PTH actions using small molecules. Moreover, a detailed understanding of the molecular circuitry used by PTH1R to exert its biologic effects will afford powerful new models to better understand the diverse actions of this important G protein coupled receptor in health and disease.
Topics: Bone and Bones; Humans; Parathyroid Hormone; Phosphotransferases; Protein Serine-Threonine Kinases; Receptor, Parathyroid Hormone, Type 1; Signal Transduction
PubMed: 35953111
DOI: 10.1016/bs.vh.2022.04.008 -
Nature Communications May 2022Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also...
Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.
Topics: Acetyl Coenzyme A; Animals; Drosophila; Drosophila Proteins; Mitochondria; Neurodegenerative Diseases; Parkinson Disease; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 35504872
DOI: 10.1038/s41467-022-30178-x -
Proceedings of the National Academy of... Jul 2022
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Phosphoenolpyruvate Sugar Phosphotransferase System
PubMed: 35867771
DOI: 10.1073/pnas.2208035119 -
The Plant Cell Jul 2022
Topics: Arabidopsis; Arabidopsis Proteins; Phosphotransferases
PubMed: 35474018
DOI: 10.1093/plcell/koac112 -
Nucleic Acids Research Jan 2021Mutations in kinases are abundant and critical to study signaling pathways and regulatory roles in human disease, especially in cancer. Somatic mutations in kinase genes...
Mutations in kinases are abundant and critical to study signaling pathways and regulatory roles in human disease, especially in cancer. Somatic mutations in kinase genes can affect drug treatment, both sensitivity and resistance, to clinically used kinase inhibitors. Here, we present a newly constructed database, KinaseMD (kinase mutations and drug response), to structurally and functionally annotate kinase mutations. KinaseMD integrates 679 374 somatic mutations, 251 522 network-rewiring events, and 390 460 drug response records curated from various sources for 547 kinases. We uniquely annotate the mutations and kinase inhibitor response in four types of protein substructures (gatekeeper, A-loop, G-loop and αC-helix) that are linked to kinase inhibitor resistance in literature. In addition, we annotate functional mutations that may rewire kinase regulatory network and report four phosphorylation signals (gain, loss, up-regulation and down-regulation). Overall, KinaseMD provides the most updated information on mutations, unique annotations of drug response especially drug resistance and functional sites of kinases. KinaseMD is accessible at https://bioinfo.uth.edu/kmd/, having functions for searching, browsing and downloading data. To our knowledge, there has been no systematic annotation of these structural mutations linking to kinase inhibitor response. In summary, KinaseMD is a centralized database for kinase mutations and drug response.
Topics: Databases, Genetic; Drug Resistance, Neoplasm; Molecular Sequence Annotation; Mutation; Phosphorylation; Phosphotransferases; Protein Kinase Inhibitors; User-Computer Interface
PubMed: 33137204
DOI: 10.1093/nar/gkaa945