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Microbiology (Reading, England) Nov 2022ATP-binding cassette (ABC) transporters are one of the largest protein superfamilies and are found in all living organisms. These transporters use the energy from ATP... (Review)
Review
ATP-binding cassette (ABC) transporters are one of the largest protein superfamilies and are found in all living organisms. These transporters use the energy from ATP binding and hydrolysis to transport various substrates. In this review, we focus on the structural and functional aspects of ABC transporters, with special emphasis on type VII ABC transporters, a newly defined class possessing characteristic structures. A notable feature of type VII ABC transporters is that they assemble into tripartite complexes that span both the inner and outer membranes of Gram-negative bacteria. One of the original type VII ABC transporters, which possesses all characteristic features of this class, is the macrolide efflux transporter MacB. Recent structural analyses of MacB and homologue proteins revealed the unique mechanisms of substrate translocation by type VII ABC transporters.
Topics: ATP-Binding Cassette Transporters; Models, Molecular; Membrane Transport Proteins; Biological Transport; Adenosine Triphosphate
PubMed: 36409601
DOI: 10.1099/mic.0.001257 -
International Journal of Molecular... Aug 2022Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but... (Review)
Review
Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but they transport only a handful of substrates, mainly glucose and fructose. This overlap and redundancy contradict the natural tendency of cells to conserve energy and resources, and has led researchers to hypothesize that different GLUTs partake in more metabolic roles than just sugar transport into cells. Understanding those roles will lead to better therapeutics for a wide variety of diseases and disorders. In this review we highlight recent discoveries of the role GLUTs play in different diseases and disease treatments.
Topics: Animals; Biological Transport; Fructose; Glucose; Glucose Transport Proteins, Facilitative; Mammals; Membrane Transport Proteins
PubMed: 35955833
DOI: 10.3390/ijms23158698 -
Nature Nov 2019At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and self-DNA, respectively. Despite the structural and functional...
At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and self-DNA, respectively. Despite the structural and functional similarities between these receptors, their contributions to autoimmune diseases such as systemic lupus erythematosus can differ. For example, TLR7 and TLR9 have opposing effects in mouse models of systemic lupus erythematosus-disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice. However, the mechanisms of negative regulation that differentiate between TLR7 and TLR9 are unknown. Here we report a function for the TLR trafficking chaperone UNC93B1 that specifically limits signalling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. Mutations in UNC93B1 that lead to enhanced TLR7 signalling also disrupt binding of UNC93B1 to syntenin-1, which has been implicated in the biogenesis of exosomes. Both UNC93B1 and TLR7 can be detected in exosomes, suggesting that recruitment of syntenin-1 by UNC93B1 facilitates the sorting of TLR7 into intralumenal vesicles of multivesicular bodies, which terminates signalling. Binding of syntenin-1 requires phosphorylation of UNC93B1 and provides a mechanism for dynamic regulation of TLR7 activation and signalling. Thus, UNC93B1 not only enables the proper trafficking of nucleic acid-sensing TLRs, but also sets the activation threshold of potentially self-reactive TLR7.
Topics: Animals; Autoimmunity; Cell Line; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Phosphorylation; Polymorphism, Single Nucleotide; Signal Transduction; Syntenins; Toll-Like Receptor 7
PubMed: 31546246
DOI: 10.1038/s41586-019-1612-6 -
Clinical Pharmacokinetics Feb 2022Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate).... (Review)
Review
Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad), administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years), are used to treat patients with relapsing multiple sclerosis. Cladribine has been shown to be a substrate of various nucleoside transporters (NTs). Intestinal absorption and distribution of cladribine throughout the body appear to be essentially mediated by equilibrative NTs (ENTs) and concentrative NTs (CNTs), specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Other efficient transporters of cladribine are the ABC efflux transporters, specifically breast cancer resistance protein, which likely modulates the oral absorption and renal excretion of cladribine. A key transporter for the intracellular uptake of cladribine into B and T-lymphocytes is ENT1 with ancillary contributions of ENT2 and CNT2. Transporter-based drug interactions affecting absorption and target cellular uptake of a prodrug such as cladribine are likely to reduce systemic bioavailability and target cell exposure, thereby possibly hampering clinical efficacy. In order to manage optimized therapy, i.e., to ensure uncompromised target cell uptake to preserve the full therapeutic potential of cladribine, it is important that clinicians are aware of the existence of NT-inhibiting medicinal products, various lifestyle drugs, and food components. This article reviews the existing knowledge on inhibitors of NT, which may alter cladribine absorption, distribution, and uptake into target cells, thereby summarizing the existing knowledge on optimized methods of administration and concomitant drugs that should be avoided during cladribine treatment.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cladribine; Drug Interactions; Equilibrative Nucleoside Transporter 1; Humans; Membrane Transport Proteins; Neoplasm Proteins; Nucleoside Transport Proteins
PubMed: 34894346
DOI: 10.1007/s40262-021-01089-9 -
American Journal of Physiology. Renal... Feb 2020The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with... (Review)
Review
The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na-K-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na-K-2Cl cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca and Mg are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.
Topics: Adaptation, Physiological; Animals; Evolution, Molecular; Humans; Kidney Cortex; Kidney Medulla; Loop of Henle; Membrane Transport Proteins; Renal Reabsorption; Species Specificity; Water-Electrolyte Balance
PubMed: 31841389
DOI: 10.1152/ajprenal.00261.2019 -
Proceedings of the National Academy of... Jul 2022Bacterial pathogens acquire heme from the host hemoglobin as an iron nutrient for their virulence and proliferation in blood. Concurrently, they encounter cytotoxic-free...
Bacterial pathogens acquire heme from the host hemoglobin as an iron nutrient for their virulence and proliferation in blood. Concurrently, they encounter cytotoxic-free heme that escapes the heme-acquisition process. To overcome this toxicity, many gram-positive bacteria employ an ATP-binding cassette heme-dedicated efflux pump, HrtBA in the cytoplasmic membranes. Although genetic analyses have suggested that HrtBA expels heme from the bacterial membranes, the molecular mechanism of heme efflux remains elusive due to the lack of protein studies. Here, we show the biochemical properties and crystal structures of HrtBA, alone and in complex with heme or an ATP analog, and we reveal how HrtBA extracts heme from the membrane and releases it. HrtBA consists of two cytoplasmic HrtA ATPase subunits and two transmembrane HrtB permease subunits. A heme-binding site is formed in the HrtB dimer and is laterally accessible to heme in the outer leaflet of the membrane. The heme-binding site captures heme from the membrane using a glutamate residue of either subunit as an axial ligand and sequesters the heme within the rearranged transmembrane helix bundle. By ATP-driven HrtA dimerization, the heme-binding site is squeezed to extrude the bound heme. The mechanism sheds light on the detoxification of membrane-bound heme in this bacterium.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Bacterial Proteins; Corynebacterium diphtheriae; Heme; Membrane Transport Proteins; Protein Conformation; Protein Multimerization
PubMed: 35767641
DOI: 10.1073/pnas.2123385119 -
Biomolecules Nov 2022The transmembrane transport of weak acid and base metabolites depends on the local pH conditions that affect the protonation status of the substrates and the... (Review)
Review
The transmembrane transport of weak acid and base metabolites depends on the local pH conditions that affect the protonation status of the substrates and the availability of co-substrates, typically protons. Different protein designs ensure the attraction of substrates and co-substrates to the transporter entry sites. These include electrostatic surface charges on the transport proteins and complexation with seemingly transport-unrelated proteins that provide substrate and/or proton antenna, or enzymatically generate substrates in place. Such protein assemblies affect transport rates and directionality. The lipid membrane surface also collects and transfers protons. The complexity in the various systems enables adjustability and regulation in a given physiological or pathophysiological situation. This review describes experimentally shown principles in the attraction and facilitation of weak acid and base transport substrates, including monocarboxylates, ammonium, bicarbonate, and arsenite, plus protons as a co-substrate.
Topics: Protons; Biological Transport; Membrane Transport Proteins; Hydrogen-Ion Concentration
PubMed: 36551222
DOI: 10.3390/biom12121794 -
Microbiology (Reading, England) Oct 2023Multidrug efflux pumps are molecular machines that sit in the bacterial cell membrane and pump molecules out from either the periplasm or cytoplasm to outside the cell....
Multidrug efflux pumps are molecular machines that sit in the bacterial cell membrane and pump molecules out from either the periplasm or cytoplasm to outside the cell. While involved in a variety of biological roles, they are primarily known for their contribution to antibiotic resistance by limiting the intracellular accumulation of antimicrobial compounds within bacteria. These transporters are often overexpressed in clinical isolates, leading to multidrug-resistant phenotypes. Efflux pumps are classified into several families based on their structure and understanding the characteristics of each family is important for the development of novel therapies to restore antibiotic potency.
Topics: Humans; Cytoplasm; Periplasm; Cell Membrane; Anti-Bacterial Agents; Membrane Transport Proteins
PubMed: 37787650
DOI: 10.1099/mic.0.001370 -
Pharmacological Reports : PR Oct 2020Emerging information suggests that gastrointestinal and systemic pathology states may affect expression and function of membrane transporters in the gastrointestinal... (Review)
Review
Emerging information suggests that gastrointestinal and systemic pathology states may affect expression and function of membrane transporters in the gastrointestinal tract. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems that in some pathologies, e.g., liver or kidney failure, changes in the intestinal transporter function provide compensatory functions, eliminating substrates excreted by dysfunctional organs. A literature search was conducted on Ovid and Pubmed databases to select relevant in vitro, animal and human studies that have reported expression, protein abundance and function of intestinal drug transporters. The accumulated data suggest that gastrointestinal pathology (inflammatory bowel disease, celiac disease, cholestasis) as well as systemic pathologies (kidney failure, liver failure, hyperthyroidism, hyperparathyroidism, obesity, diabetes mellitus, systemic inflammation and Alzheimer disease) may affect drug transporter expression and function in the gastrointestinal tract. The altered status of drug transporters may provide compensatory activity in handling endogenous compounds, affect local drug actions in the gastrointestinal tract as well as impact drug bioavailability.
Topics: Animals; Biological Transport; Humans; Intestines; Membrane Transport Proteins; Pharmaceutical Preparations
PubMed: 32715435
DOI: 10.1007/s43440-020-00139-6 -
International Journal of Molecular... Jul 2022Membrane transport proteins are widely present in all living organisms, however, their function, transported substrate, and mechanism of action are unknown. Here we use...
Membrane transport proteins are widely present in all living organisms, however, their function, transported substrate, and mechanism of action are unknown. Here we use diverse bioinformatics tools to investigate the evolution of MTPs, analyse domain organisation and loop topology, and study the comparative alignment of modelled 3D structures. Our results suggest a high level of conservancy between MTPs from different taxa on both amino acids and structural levels, which imply some degree of functional similarities. The presence of loop/s of different lengths in various positions suggests tax-on-specific adaptation to transported substrates, intracellular localisation, accessibility for post-translation modifications, and interaction with other proteins. The comparison of modelled structures proposes close relations and a common origin for MTP and Na/H exchanger. Further, a high level of amino acid similarity and identity between archaeal and bacterial MTPs and Na/H exchangers imply conservancy of ion transporting function at least for archaeal and bacterial MTPs.
Topics: Amino Acid Sequence; Biological Transport; Ion Transport; Membrane Transport Proteins; Sodium-Hydrogen Exchangers
PubMed: 35897663
DOI: 10.3390/ijms23158094