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The Journal of Experimental Medicine Aug 2024Genetic variation in UNC93B1, a key component in TLR trafficking, can lead to autoinflammation caused by increased TLR activity. Analysis of seven patient variants...
Genetic variation in UNC93B1, a key component in TLR trafficking, can lead to autoinflammation caused by increased TLR activity. Analysis of seven patient variants combined with a comprehensive alanine screen revealed that different regions of UNC93B1 selectively regulate different TLRs (Rael et al. https://doi.org/10.1084/jem.20232005; David et al. https://doi.org/10.1084/jem.20232066).
Topics: Humans; Toll-Like Receptors; Membrane Transport Proteins; Protein Transport; Animals
PubMed: 38869499
DOI: 10.1084/jem.20240841 -
Research in Microbiology 2018Efflux pumps are systems devoted to the extrusion of noxious compounds. In this review, we discuss the various strategies that have thus far been undertaken for the... (Review)
Review
Efflux pumps are systems devoted to the extrusion of noxious compounds. In this review, we discuss the various strategies that have thus far been undertaken for the investigation of efflux pumps after reconstitution into liposomes. It is challenging to uncover mechanisms and dynamics of efflux pumps due to a number of characteristics: their function depends on the correct assembly of three components and they span two adjacent membranes whose lipid compositions are very different. In addition, efflux pumps are active transporters that need energy to work. We present possible lines of improvement for the study of such systems and provide insights into future goals and challenges of efflux pump reconstitution and transport.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biological Transport; Gram-Negative Bacteria; Liposomes; Membrane Transport Proteins; Multigene Family
PubMed: 29217371
DOI: 10.1016/j.resmic.2017.11.004 -
Biochemical Society Transactions Aug 2020Membrane transporters control the movement and distribution of solutes, including the disposal or compartmentation of toxic substances that accumulate in plants under... (Review)
Review
Membrane transporters control the movement and distribution of solutes, including the disposal or compartmentation of toxic substances that accumulate in plants under adverse environmental conditions. In this minireview, in the light of the approaching 100th anniversary of unveiling the significance of boron to plants (K. Warington, 1923; Ann. Bot.37, 629) we discuss the current state of the knowledge on boron transport systems that plants utilise to combat boron toxicity. These transport proteins include: (i) nodulin-26-like intrinsic protein-types of aquaporins, and (ii) anionic efflux (borate) solute carriers. We describe the recent progress made on the structure-function relationships of these transport proteins and point out that this progress is integral to quantitative considerations of the transporter's roles in tissue boron homeostasis. Newly acquired knowledge at the molecular level has informed on the transport mechanics and conformational states of boron transport systems that can explain their impact on cell biology and whole plant physiology. We expect that this information will form the basis for engineering transporters with optimised features to alleviate boron toxicity tolerance in plants exposed to suboptimal soil conditions for sustained food production.
Topics: Boron; Membrane Transport Proteins; Plant Proteins; Plants; Protein Conformation; Soil
PubMed: 32779723
DOI: 10.1042/BST20200164 -
International Journal of Molecular... Mar 2021Active transport of sugars into bacteria occurs through symporters driven by ion gradients. is the most well-studied proton sugar symporter, whereas is the most... (Review)
Review
Active transport of sugars into bacteria occurs through symporters driven by ion gradients. is the most well-studied proton sugar symporter, whereas is the most characterized sodium sugar symporter. These are members of the major facilitator (MFS) and the amino acid-Polyamine organocation (APS) transporter superfamilies. While there is no structural homology between these transporters, they operate by a similar mechanism. They are nano-machines driven by their respective ion electrochemical potential gradients across the membrane. has 12 transmembrane helices (TMs) organized in two 6-TM bundles, each containing two 3-helix TM repeats. has a core structure of 10 TM helices organized in two inverted repeats (TM 1-5 and TM 6-10). In each case, a single sugar is bound in a central cavity and sugar selectivity is determined by hydrogen- and hydrophobic- bonding with side chains in the binding site. In vSGLT, the sodium-binding site is formed through coordination with carbonyl- and hydroxyl-oxygens from neighboring side chains, whereas in the proton (HO) site is thought to be a single glutamate residue (Glu325). The remaining challenge for both transporters is to determine how ion electrochemical potential gradients drive uphill sugar transport.
Topics: Binding Sites; Biological Transport, Active; Escherichia coli Proteins; Glucose; Lactose; Membrane Transport Proteins; Models, Molecular; Monosaccharide Transport Proteins; Protein Conformation; Sodium-Glucose Transport Proteins; Sugars; Symporters
PubMed: 33808202
DOI: 10.3390/ijms22073572 -
European Biophysics Journal : EBJ Oct 2017Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence... (Review)
Review
Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man's discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these responses involves the use of antibiotic efflux transporters. At the single cell level, it is becoming apparent that the use of efflux pumps is the first line of defence against an antibiotic, as these pumps decrease the intracellular level of antibiotic while the cell activates the various other levels of protection. This frontline of defence involves a coordinated network of efflux transporters. In the future, inhibition of this efflux transporter network, as a target for novel antibiotic therapy, will require the isolation and then biochemical/biophysical characterisation of each pump against all known and new antibiotics. This depth of knowledge is required so that we can fully understand and tackle the mechanisms of developing antimicrobial resistance.
Topics: Adaptation, Physiological; Anti-Bacterial Agents; Bacteria; Biofilms; Drug Resistance, Bacterial; Membrane Transport Proteins
PubMed: 28710521
DOI: 10.1007/s00249-017-1238-2 -
Biochemical and Biophysical Research... Oct 2014Multidrug resistance (MDR) refers to the capability of bacterial pathogens to withstand lethal doses of structurally diverse drugs which are capable of eradicating... (Review)
Review
Multidrug resistance (MDR) refers to the capability of bacterial pathogens to withstand lethal doses of structurally diverse drugs which are capable of eradicating non-resistant strains. MDR has been identified as a major threat to the public health of human being by the World Health Organization (WHO). Among the four general mechanisms that cause antibiotic resistance including target alteration, drug inactivation, decreased permeability and increased efflux, drug extrusion by the multidrug efflux pumps serves as an important mechanism of MDR. Efflux pumps not only can expel a broad range of antibiotics owing to their poly-substrate specificity, but also drive the acquisition of additional resistance mechanisms by lowering intracellular antibiotic concentration and promoting mutation accumulation. Over-expression of multidrug efflux pumps have been increasingly found to be associated with clinically relevant drug resistance. On the other hand, accumulating evidence has suggested that efflux pumps also have physiological functions in bacteria and their expression is subject tight regulation in response to various of environmental and physiological signals. A comprehensive understanding of the mechanisms of drug extrusion, and regulation and physiological functions of efflux pumps is essential for the development of anti-resistance interventions. In this review, we summarize the development of these research areas in the recent decades and present the pharmacological exploitation of efflux pump inhibitors as a promising anti-drug resistance intervention.
Topics: Animals; Bacteria; Bacterial Proteins; Biofilms; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Genes, MDR; Humans; Membrane Transport Proteins; Models, Molecular; Virulence
PubMed: 24878531
DOI: 10.1016/j.bbrc.2014.05.090 -
FEBS Letters Dec 2020To remove xenobiotics from the periplasmic space, Gram-negative bacteria utilise unique tripartite efflux systems in which a molecular engine in the plasma membrane... (Review)
Review
To remove xenobiotics from the periplasmic space, Gram-negative bacteria utilise unique tripartite efflux systems in which a molecular engine in the plasma membrane connects to periplasmic and outer membrane subunits. Substrates bind to periplasmic sections of the engine or sometimes to the periplasmic subunits. Then, the tripartite machines undergo conformational changes that allow the movement of the substrates down the substrate translocation pathway to the outside of the cell. The transmembrane (TM) domains of the tripartite resistance-nodulation-drug-resistance (RND) transporters drive these conformational changes by converting proton motive force into mechanical motion. Similarly, the TM domains of tripartite ATP-binding cassette (ABC) transporters transmit mechanical movement associated with nucleotide binding and hydrolysis at the nucleotide-binding domains to the relevant subunits in the periplasm. In this way, metabolic energy is coupled to periplasmic alternating-access mechanisms to achieve substrate transport across the outer membrane.
Topics: ATP-Binding Cassette Transporters; Bacterial Proteins; Membrane Transport Proteins; Models, Molecular; Multidrug Resistance-Associated Proteins; Periplasm
PubMed: 32936941
DOI: 10.1002/1873-3468.13929 -
International Journal of Molecular... Mar 2021Cytokinins are a class of phytohormones, signalling molecules specific to plants. They act as regulators of diverse physiological processes in complex signalling... (Review)
Review
Cytokinins are a class of phytohormones, signalling molecules specific to plants. They act as regulators of diverse physiological processes in complex signalling pathways. It is necessary for plants to continuously regulate cytokinin distribution among different organs, tissues, cells, and compartments. Such regulatory mechanisms include cytokinin biosynthesis, metabolic conversions and degradation, as well as cytokinin membrane transport. In our review, we aim to provide a thorough picture of the latter. We begin by summarizing cytokinin structures and physicochemical properties. Then, we revise the elementary thermodynamic and kinetic aspects of cytokinin membrane transport. Next, we review which membrane-bound carrier proteins and protein families recognize cytokinins as their substrates. Namely, we discuss the families of "equilibrative nucleoside transporters" and "purine permeases", which translocate diverse purine-related compounds, and proteins AtPUP14, AtABCG14, AtAZG1, and AtAZG2, which are specific to cytokinins. We also address long-distance cytokinin transport. Putting all these pieces together, we finally discuss cytokinin distribution as a net result of these processes, diverse in their physicochemical nature but acting together to promote plant fitness.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Cell Membrane; Cytokinins; Gene Expression Regulation, Plant; Homeostasis; Hydrophobic and Hydrophilic Interactions; Kinetics; Membrane Transport Proteins; Plant Growth Regulators; Plant Roots; Plant Shoots; Signal Transduction; Thermodynamics
PubMed: 33810428
DOI: 10.3390/ijms22073428 -
Microbiology (Reading, England) Nov 2023The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While... (Review)
Review
The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off. This includes small molecule feedback, inhibition by interaction with small peptides, regulation through binding larger signal transduction proteins and, finally, the emerging area of controlled proteolysis. Many of these examples have been discovered in the context of metal transport, which has to finely balance active accumulation of elements that are essential for growth but can also quickly become toxic if intracellular homeostasis is not tightly controlled. Consistent with this, these transporters appear to be regulated at multiple levels. Finally, we find common regulatory themes, most often through the fusion of additional regulatory domains to transporters, which suggest the potential for even more widespread regulation of transporter activity in biology.
Topics: Membrane Transport Proteins; Cell Membrane; Bacteria
PubMed: 37948297
DOI: 10.1099/mic.0.001412 -
Human Molecular Genetics May 2022The most frequent genetic cause of focal epilepsies is variations in the GAP activity toward RAGs 1 complex genes DEP domain containing 5 (DEPDC5), nitrogen permease...
The most frequent genetic cause of focal epilepsies is variations in the GAP activity toward RAGs 1 complex genes DEP domain containing 5 (DEPDC5), nitrogen permease regulator 2-like protein (NPRL2) and nitrogen permease regulator 3-like protein (NPRL3). Because these variations are frequent and associated with a broad spectrum of focal epilepsies, a unique pathology categorized as GATORopathy can be conceptualized. Animal models recapitulating the clinical features of patients are essential to decipher GATORopathy. Although several genetically modified animal models recapitulate DEPDC5-related epilepsy, no models have been reported for NPRL2- or NPRL3-related epilepsies. Here, we conditionally deleted Nprl2 and Nprl3 from the dorsal telencephalon in mice [Emx1cre/+; Nprl2f/f (Nprl2-cKO) and Emx1cre/+; Nprl3f/f (Nprl3-cKO)] and compared their phenotypes with Nprl2+/-, Nprl3+/- and Emx1cre/+; Depdc5f/f (Depdc5-cKO) mice. Nprl2-cKO and Nprl3-cKO mice recapitulated the major abnormal features of patients-spontaneous seizures, and dysmorphic enlarged neuronal cells with increased mechanistic target of rapamycin complex 1 signaling-similar to Depdc5-cKO mice. Chronic postnatal rapamycin administration dramatically prolonged the survival period and inhibited seizure occurrence but not enlarged neuronal cells in Nprl2-cKO and Nprl3-cKO mice. However, the benefit of rapamycin after withdrawal was less durable in Nprl2- and Nprl3-cKO mice compared with Depdc5-cKO mice. Further studies using these conditional knockout mice will be useful for understanding GATORopathy and for the identification of novel therapeutic targets.
Topics: Animals; Disease Models, Animal; Epilepsies, Partial; Epilepsy; GTPase-Activating Proteins; Membrane Transport Proteins; Mice; Mice, Knockout; Mutation; Nitrogen; Seizures; Sirolimus; Telencephalon; Tumor Suppressor Proteins
PubMed: 34965576
DOI: 10.1093/hmg/ddab337