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Nature Cell Biology Jun 2022Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a...
Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a ubiquitous form of endocytosis of particular importance for immune and cancer cells, generates large vacuoles that can be followed optically. Shrinkage of macrophage macropinosomes depends on TPC-mediated Na efflux and Cl exit through unknown channels. Relieving osmotic pressure facilitates vesicle budding, positioning osmotic shrinkage upstream of vesicular sorting and trafficking. Here we identify the missing macrophage Cl channel as the proton-activated Cl channel ASOR/TMEM206. ASOR activation requires Na-mediated depolarization and luminal acidification by redundant transporters including H-ATPases and CLC 2Cl/H exchangers. As corroborated by mathematical modelling, feedback loops requiring the steep voltage and pH dependencies of ASOR and CLCs render vacuole resolution resilient towards transporter copy numbers. TMEM206 disruption increased albumin-dependent survival of cancer cells. Our work suggests a function for the voltage and pH dependence of ASOR and CLCs, provides a comprehensive model for ion-transport-dependent vacuole maturation and reveals biological roles of ASOR.
Topics: Anions; Chloride Channels; Hydrogen-Ion Concentration; Ion Transport; Protons
PubMed: 35590106
DOI: 10.1038/s41556-022-00912-0 -
Chemical Society Reviews Sep 2022Entangling strands in a well-ordered manner can produce useful effects, from shoelaces and fishing nets to brown paper packages tied up with strings. At the nanoscale,... (Review)
Review
Entangling strands in a well-ordered manner can produce useful effects, from shoelaces and fishing nets to brown paper packages tied up with strings. At the nanoscale, non-crystalline polymer chains of sufficient length and flexibility randomly form tangled mixtures containing open knots of different sizes, shapes and complexity. However, discrete molecular knots of precise topology can also be obtained by controlling the number, sequence and stereochemistry of strand crossings: orderly molecular entanglements. During the last decade, substantial progress in the nascent field of molecular nanotopology has been made, with general synthetic strategies and new knotting motifs introduced, along with insights into the properties and functions of ordered tangle sequences. Conformational restrictions imparted by knotting can induce allostery, strong and selective anion binding, catalytic activity, lead to effective chiral expression across length scales, binding modes in conformations efficacious for drug delivery, and facilitate mechanical function at the molecular level. As complex molecular topologies become increasingly synthetically accessible they have the potential to play a significant role in molecular and materials design strategies. We highlight particular examples of molecular knots to illustrate why these are a few of our favourite things.
Topics: Anions; Polymers
PubMed: 35979715
DOI: 10.1039/d2cs00323f -
Chemical Reviews Mar 2020Using anions to induce molecular structure is a rapidly growing area of dynamic and switchable supramolecular chemistry. The emphasis of this review is on helical anion... (Review)
Review
Using anions to induce molecular structure is a rapidly growing area of dynamic and switchable supramolecular chemistry. The emphasis of this review is on helical anion foldamers in solution, and many of the beautiful complexes described herein are accentuated by their crystal structures. Anion foldamers are defined as single- or multistrand complexes-often helical-that incorporate one or more anions. The review begins by discussing foldamer structure and nomenclature and follows with discourse on the anions which are employed. Recent advances in functional foldamers that bind a single anion are examined, including: induced chirality, stimuli-responsive dynamics, fluorescence changes, organocatalysis, anion transport, and halogen bonding. The review then inspects multianion foldamers, and this section is organized by the number of strands within the foldamer-from single- to triple-strand foldamers. Finally, the review is punctuated by recent hydrogen- and halogen-bonding triple-strand anion foldamers.
Topics: Anions; Molecular Conformation; Organic Chemicals; Polymers
PubMed: 32039583
DOI: 10.1021/acs.chemrev.9b00583 -
Journal of the American Chemical Society Mar 2022Spatial sequestration of molecules is a prerequisite for the complexity of biological systems, enabling the occurrence of numerous, often non-compatible chemical...
Spatial sequestration of molecules is a prerequisite for the complexity of biological systems, enabling the occurrence of numerous, often non-compatible chemical reactions and processes in one cell at the same time. Inspired by this compartmentalization concept, chemists design and synthesize artificial nanocontainers (capsules and cages) and use them to mimic the biological complexity and for new applications in recognition, separation, and catalysis. Here, we report the formation of large closed-shell species by interactions of well-known polyphenolic macrocycles with anions. It has been known since many years that C-alkyl resorcin[4]arenes () and C-alkyl pyrogallol[4]arenes () narcissistically self-assemble in nonpolar solvents to form hydrogen-bonded capsules. Here, we show a new interaction model that additionally involves anions as interacting partners and leads to even larger capsular species. Diffusion-ordered spectroscopy and titration experiments indicate that the anion-sealed species have a diameter of >26 Å and suggest stoichiometry ()(X) and tight ion pairing with cations. This self-assembly is effective in a nonpolar environment (THF and benzene but not in chloroform), however, requires initiation by mechanochemistry (dry milling) in the case of non-compatible solubility. Notably, it is common among various polyphenolic macrocycles () having diverse geometries and various conformational lability.
Topics: Anions; Calixarenes; Pyrogallol; Resorcinols
PubMed: 35274940
DOI: 10.1021/jacs.1c11793 -
Nature Communications Aug 2022The quantification of anion binding by molecular receptors within lipid bilayers remains challenging. Here we measure anion binding in lipid bilayers by creating a...
The quantification of anion binding by molecular receptors within lipid bilayers remains challenging. Here we measure anion binding in lipid bilayers by creating a fluorescent macrocycle featuring a strong sulfate affinity. We find the determinants of anion binding in lipid bilayers to be different from those expected that govern anion binding in solution. Charge-dense anions HPO and Cl that prevail in dimethyl sulfoxide fail to bind to the macrocycle in lipids. In stark contrast, ClO and I that hardly bind in dimethyl sulfoxide show surprisingly significant affinities for the macrocycle in lipids. We reveal a lipid bilayer anion binding principle that depends on anion polarisability and bilayer penetration depth of complexes leading to unexpected advantages of charge-diffuse anions. These insights enhance our understanding of how biological systems select anions and guide the design of functional molecular systems operating at biomembrane interfaces.
Topics: Anions; Dimethyl Sulfoxide; Lipid Bilayers; Sulfates
PubMed: 35941124
DOI: 10.1038/s41467-022-32403-z -
Biochimica Et Biophysica Acta.... Feb 2022Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium....
Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon imine protonation at pH 4.5. The rate-determining process of the pH switch, however, was not examined. We here develop a new series of PTSCs and demonstrate their conformational behaviour by X-ray crystallographic analysis and pH-switchable anion transport properties by liposomal assays. We report the surprising finding that the protonated PTSCs are extremely selective for halides over oxyanions in membrane transport. Owing to the high chloride over nitrate selectivity, the pH-dependent chloride/nitrate exchange of PTSCs originates from the rate-limiting nitrate transport process being inhibited at neutral pH.
Topics: Anions; Chlorides; Crystallography, X-Ray; Hydrogen-Ion Concentration; Ion Transport; Kinetics; Nitrates; Protons; Thiosemicarbazones
PubMed: 34861222
DOI: 10.1016/j.bbamem.2021.183828 -
International Journal of Molecular... Sep 2022The increasing concentration of CO in the atmosphere is related to global climate change. Carbon capture, utilization, and storage (CCUS) is an important technology to... (Review)
Review
The increasing concentration of CO in the atmosphere is related to global climate change. Carbon capture, utilization, and storage (CCUS) is an important technology to reduce CO emissions and to deal with global climate change. The development of new materials and technologies for efficient CO capture has received increasing attention among global researchers. Ionic liquids (ILs), especially functionalized ILs, with such unique properties as almost no vapor pressure, thermal- and chemical-stability, non-flammability, and tunable properties, have been used in CCUS with great interest. This paper focuses on the development of functionalized ILs for CO capture in the past decade (2012~2022). Functionalized ILs, or task-specific ILs, are ILs with active sites on cations or/and anions. The main contents include three parts: cation-functionalized ILs, anion-functionalized ILs, and cation-anion dual-functionalized ILs for CO capture. In addition, classification, structures, and synthesis of functionalized ILs are also summarized. Finally, future directions, concerns, and prospects for functionalized ILs in CCUS are discussed. This review is beneficial for researchers to obtain an overall understanding of CO-philic ILs. This work will open a door to develop novel IL-based solvents and materials for the capture and separation of other gases, such as SO, HS, NOx, NH, and so on.
Topics: Anions; Carbon; Carbon Dioxide; Cations; Ionic Liquids; Solvents
PubMed: 36232702
DOI: 10.3390/ijms231911401 -
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 -
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 -
The Journal of General Physiology Aug 2022Numerous essential physiological processes depend on the TMEM16A-mediated Ca2+-activated chloride fluxes. Extensive structure-function studies have helped to elucidate...
Numerous essential physiological processes depend on the TMEM16A-mediated Ca2+-activated chloride fluxes. Extensive structure-function studies have helped to elucidate the Ca2+ gating mechanism of TMEM16A, revealing a Ca2+-sensing element close to the anion pore that alters conduction. However, substrate selection and the substrate-gating relationship in TMEM16A remain less explored. Here, we study the gating-permeant anion relationship on mouse TMEM16A expressed in HEK 293 cells using electrophysiological recordings coupled with site-directed mutagenesis. We show that the apparent Ca2+ sensitivity of TMEM16A increased with highly permeant anions and SCN- mole fractions, likely by stabilizing bound Ca2+. Conversely, mutations at crucial gating elements, including the Ca2+-binding site 1, the transmembrane helix 6 (TM6), and the hydrophobic gate, impaired the anion permeability and selectivity of TMEM16A. Finally, we found that, unlike anion-selective wild-type channels, the voltage dependence of unselective TMEM16A mutant channels was less sensitive to SCN-. Therefore, our work identifies structural determinants of selectivity at the Ca2+ site, TM6, and hydrophobic gate and reveals a reciprocal regulation of gating and selectivity. We suggest that this regulation is essential to set ionic selectivity and the Ca2+ and voltage sensitivities in TMEM16A.
Topics: Animals; Anions; Anoctamin-1; Calcium; Chloride Channels; HEK293 Cells; Humans; Ion Channel Gating; Mice; Neoplasm Proteins
PubMed: 35687042
DOI: 10.1085/jgp.202113027