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Handbook of Experimental Pharmacology 2024Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include... (Review)
Review
Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include chloride, bicarbonate, and sulfate, but also small organic dicarboxylates such as fumarate and oxalate. The human genome encodes ten functional homologs, several of which are causally associated with severe human diseases, highlighting their physiological importance. Here, we review novel insights into the structure and function of SLC26 proteins and summarize the physiological relevance of human members.
Topics: Humans; Sulfate Transporters; Anion Transport Proteins; Anions; Biological Transport
PubMed: 37947907
DOI: 10.1007/164_2023_698 -
Cell Reports Aug 2023Volume-regulated anion channels (VRACs) are hexamers of LRRC8 proteins that are crucial for cell volume regulation. N termini (NTs) of the obligatory LRRC8A subunit...
Volume-regulated anion channels (VRACs) are hexamers of LRRC8 proteins that are crucial for cell volume regulation. N termini (NTs) of the obligatory LRRC8A subunit modulate VRACs activation and ion selectivity, but the underlying mechanisms remain poorly understood. Here, we report a 2.8-Å cryo-electron microscopy structure of human LRRC8A that displays well-resolved NTs. Amino-terminal halves of NTs fold back into the pore and constrict the permeation path, thereby determining ion selectivity together with an extracellular selectivity filter with which it works in series. They also interact with pore-surrounding helices and support their compact arrangement. The C-terminal halves of NTs interact with intracellular loops that are crucial for channel activation. Molecular dynamics simulations indicate that low ionic strength increases NT mobility and expands the radial distance between pore-surrounding helices. Our work suggests an unusual pore architecture with two selectivity filters in series and a mechanism for VRAC activation by cell swelling.
Topics: Humans; Cryoelectron Microscopy; Membrane Proteins; Anions; Cell Size; Osmolar Concentration
PubMed: 37543949
DOI: 10.1016/j.celrep.2023.112926 -
International Journal of Molecular... Aug 2023In the last few decades, reticular chemistry has grown significantly as a field of porous crystalline molecular materials. Scientists have attempted to create the ideal... (Review)
Review
In the last few decades, reticular chemistry has grown significantly as a field of porous crystalline molecular materials. Scientists have attempted to create the ideal platform for analyzing distinct anions based on optical sensing techniques (chromogenic and fluorogenic) by assembling different metal-containing units with suitable organic linking molecules and different organic molecules to produce crystalline porous materials. This study presents novel platforms for anion recognition based on reticular chemistry with high selectivity, sensitivity, electronic tunability, structural recognition, strong emission, and thermal and chemical stability. The key materials for reticular chemistry, Metal-Organic Frameworks (MOFs), Zeolitic Imidazolate Frameworks (ZIFs), and Covalent-Organic Frameworks (COFs), and the pre- and post-synthetic modification of the linkers and the metal oxide clusters for the selective detection of the anions, have been discussed. The mechanisms involved in sensing are also discussed.
Topics: Anions; Oxides; Electronics; Metal-Organic Frameworks; Porosity
PubMed: 37685850
DOI: 10.3390/ijms241713045 -
The New Phytologist Sep 2023Plant transpiration is controlled by stomata, with S- and R-type anion channels playing key roles in guard cell action. Arabidopsis mutants lacking the ALMT12/QUAC1...
Plant transpiration is controlled by stomata, with S- and R-type anion channels playing key roles in guard cell action. Arabidopsis mutants lacking the ALMT12/QUAC1 R-type anion channel function in guard cells show only a partial reduction in R-type channel currents. The molecular nature of these remaining R-type anion currents is still unclear. To further elucidate this, patch clamp, transcript and gas-exchange measurements were performed with wild-type (WT) and different almt mutant plants. The R-type current fraction in the almt12 mutant exhibited the same voltage dependence, susceptibility to ATP block and lacked a chloride permeability as the WT. Therefore, we asked whether the R-type anion currents in the ALMT12/QUAC1-free mutant are caused by additional ALMT isoforms. In WT guard cells, ALMT12, ALMT13 and ALMT14 transcripts were detected, whereas only ALMT13 was found expressed in the almt12 mutant. Substantial R-type anion currents still remained active in the almt12/13 and almt12/14 double mutants as well as the almt12/13/14 triple mutant. In good agreement, CO -triggered stomatal closure required the activity of ALMT12 but not ALMT13 or ALMT14. The results suggest that, with the exception of ALMT12, channel species other than ALMTs carry the guard cell R-type anion currents.
Topics: Arabidopsis Proteins; Plant Stomata; Arabidopsis; Anions; Abscisic Acid
PubMed: 37434346
DOI: 10.1111/nph.19124 -
Nature Communications Nov 2023Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast...
Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling "valve" to facilitate T cell activation.
Topics: Signal Transduction; Cell Size; T-Lymphocytes; Anions; Receptors, Antigen, T-Cell
PubMed: 37925509
DOI: 10.1038/s41467-023-42817-y -
International Journal of Molecular... May 2024A comprehensive thermodynamic and structural study of the complexation affinities of tetra (), penta (), and hexaphenylalanine () linear peptides towards several...
A comprehensive thermodynamic and structural study of the complexation affinities of tetra (), penta (), and hexaphenylalanine () linear peptides towards several inorganic anions in acetonitrile (MeCN) and ,-dimethylformamide (DMF) was carried out. The influence of the chain length on the complexation thermodynamics and structural changes upon anion binding are particularly addressed here. The complexation processes were characterized by means of spectrofluorimetric, H NMR, microcalorimetric, and circular dichroism spectroscopy titrations. The results indicate that all three peptides formed complexes of 1:1 stoichiometry with chloride, bromide, hydrogen sulfate, dihydrogen phosphate (DHP), and nitrate anions in acetonitrile and DMF. In the case of hydrogen sulfate and DHP, anion complexes of higher stoichiometries were observed as well, namely those with 1:2 and 2:1 (peptide:anion) complexes. Anion-induced peptide backbone structural changes were studied by molecular dynamic simulations. The anions interacted with backbone amide protons and one of the -terminal amine protons through hydrogen bonding. Due to the anion binding, the main chain of the studied peptides changed its conformation from elongated to quasi-cyclic in all 1:1 complexes. The accomplishment of such a conformation is especially important for cyclopeptide synthesis in the head-to-tail macrocyclization step, since it is most suitable for ring closure. In addition, the studied peptides can act as versatile ionophores, facilitating transmembrane anion transport.
Topics: Anions; Thermodynamics; Peptides; Hydrogen Bonding; Molecular Dynamics Simulation; Acetonitriles; Dimethylformamide; Circular Dichroism
PubMed: 38791275
DOI: 10.3390/ijms25105235 -
Journal of Chemical Information and... Aug 2023NarK nitrate/nitrite antiporter imports nitrate (a mineral form of the essential element nitrogen) into the cell and exports nitrite (a metabolite that can be toxic in...
NarK nitrate/nitrite antiporter imports nitrate (a mineral form of the essential element nitrogen) into the cell and exports nitrite (a metabolite that can be toxic in high concentrations) out of the cell. However, many details about its operational mechanism remain poorly understood. In this work, we performed steered molecular dynamics simulations of anion translocations and quantum-chemistry model calculations of the binding sites to study the wild-type NarK protein and its R89K mutant. Our results shed light on the importance of the two strictly conserved binding-site arginine residues (R89 and R305) and two glycine-rich signature motifs (G164-M176 and G408-F419) in anion movement through the pore. We also observe conformational changes of the protein during anion migration. For the R89K mutant, our quantum calculations reveal a competition for a proton between the anion (especially nitrite) and lysine, which can potentially slow down or even trap the anion in the pore. Our findings provide a possible explanation for the striking experimental finding that the arginine-to-lysine mutation, despite preserving the charge, impedes or abolishes anion transport in such mutants of NarK and other similar nitrate/nitrite exchangers.
Topics: Nitrites; Nitrates; Anion Transport Proteins; Models, Molecular; Protein Structure, Tertiary; Binding Sites; Cell Membrane; Mutation
PubMed: 37585651
DOI: 10.1021/acs.jcim.3c00295 -
Chemical Reviews Jul 2023Anionic species are omnipresent and involved in many important biological processes. A large number of artificial anion receptors has therefore been developed. Some of... (Review)
Review
Anionic species are omnipresent and involved in many important biological processes. A large number of artificial anion receptors has therefore been developed. Some of these are capable of mediating transmembrane transport. However, where transport proteins can respond to stimuli in their surroundings, creation of synthetic receptors with stimuli-responsive functions poses a major challenge. Herein, we give a full overview of the stimulus-controlled anion receptors that have been developed thus far, including their application in membrane transport. In addition to their potential operation as membrane carriers, the use of anion recognition motifs in forming responsive membrane-spanning channels is discussed. With this review article, we intend to increase interest in transmembrane transport among scientists working on host-guest complexes and dynamic functional systems in order to stimulate further developments.
Topics: Receptors, Artificial; Biological Transport; Anions
PubMed: 37342028
DOI: 10.1021/acs.chemrev.3c00039 -
Nature Structural & Molecular Biology Nov 2023In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites....
In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for the recognition of metabolites and toxins in the nephron and their eventual urinary excretion. Inhibition of OATs is used therapeutically to improve drug efficacy and reduce nephrotoxicity. The founding member of the renal organic anion transporter family, OAT1 (also known as SLC22A6), uses the export of α-ketoglutarate (α-KG), a key intermediate in the Krebs cycle, to drive selective transport and is allosterically regulated by intracellular chloride. However, the mechanisms linking metabolite cycling, drug transport and intracellular chloride remain obscure. Here, we present cryogenic-electron microscopy structures of OAT1 bound to α-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for α-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride.
Topics: Animals; Organic Anion Transport Protein 1; Chlorides; Kidney; Biological Transport; Anions; Ketoglutaric Acids; Mammals
PubMed: 37482561
DOI: 10.1038/s41594-023-01039-y -
Nature Communications Jan 2024Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO) exchange for chloride (Cl) and is crucial for maintaining pH and salt homeostasis in the kidney,...
Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO) exchange for chloride (Cl) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl, I, HCO or in the apo-state. The structures reveal two anion-binding sites in each protomer, and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate Transporter and Anti-Sigma factor antagonist (STAS) and transmembrane domains, and mutational studies suggest a regulatory role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal directions for understanding the mechanisms of anion selectivity and exchange and their regulations by the STAS domain. This work also establishes a foundation for analyzing the pathophysiology of mutations associated with Pendred syndrome.
Topics: Humans; Bicarbonates; Chlorides; Cryoelectron Microscopy; Halogens; Hearing Loss, Sensorineural; Swine; Animals
PubMed: 38184688
DOI: 10.1038/s41467-023-44612-1