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FEBS Letters Dec 2020Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including...
Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including aminoglycoside antibiotics and antimicrobial peptides. Some family members are full-length ATP-binding cassette (ABC) transporters, whereas other members are truncated homologues that lack the nucleotide-binding domains and thus mediate ATP-independent transport. A recent cryo-EM structure of the ABC transporter Rv1819c from Mycobacterium tuberculosis has shed light on the structural basis for multi-solute transport and has provided insight into the mechanism of transport. Here, we discuss how the protein architecture makes SbmA/BacA family transporters prone to inadvertent import of antibiotics and speculate on the question which physiological processes may benefit from multi-solute transport.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Proteins; Biological Transport; Escherichia coli Proteins; Membrane Transport Proteins; Mycobacterium tuberculosis; Phosphoric Monoester Hydrolases; Substrate Specificity
PubMed: 32810294
DOI: 10.1002/1873-3468.13912 -
Acta Physiologica (Oxford, England) Nov 2023
Topics: Membrane Proteins; Kidney; Membrane Transport Proteins; Epithelial Cells; Biological Transport; Cell Membrane
PubMed: 37803943
DOI: 10.1111/apha.14052 -
Biochimica Et Biophysica Acta.... Dec 2020Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal... (Review)
Review
Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders.
Topics: Amino Acid Transport Systems, Neutral; Cystinosis; Histiocytosis; Humans; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Nucleoside Transport Proteins; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters
PubMed: 32389669
DOI: 10.1016/j.bbamem.2020.183336 -
Biochemical Society Transactions Aug 2020The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope... (Review)
Review
The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.
Topics: Antitubercular Agents; Bacterial Proteins; Biological Transport; Drug Development; Lipids; Membrane Transport Proteins; Mycolic Acids; Protein Conformation
PubMed: 32662825
DOI: 10.1042/BST20190950 -
Neurochemistry International Mar 2021Active and passive transporters constitute a gene family of approximately 2000 members. These proteins are required for import and export across the blood brain barrier,...
Active and passive transporters constitute a gene family of approximately 2000 members. These proteins are required for import and export across the blood brain barrier, clearance of neurotransmitters, inter-cellular solute transfer, and transport across the membranes of subcellular organelles. Neurologic, neurodevelopmental, and psychiatric diseases have been linked to alterations in function and/or mutations in every one of these types of transporters, and many of the transporters are targeted by therapeutics. This is the 4th biennial special edition of Neurochemistry International that originates from a scientific meeting devoted to studies of transporters and their relationship to brain function and to neurodevelopmental, neurologic, and psychiatric disorders. This meeting provides the only international forum for the presentation and discussion of cutting-edge research on brain transporters covering fundamental aspects of transporter structure, function, and trafficking. Scientists describe the novel approaches being used to link this information to physiology/circuit function and behavior. The meeting also addresses translational topics surrounding mouse models of brain transporter disorders, novel human brain disorders arising from transporter mutations, and innovative therapeutic approaches centered on modification of transporter function. This special issue includes a sampling of review articles that address timely questions of the field and several primary research articles.
Topics: Animals; Blood-Brain Barrier; Brain; Humans; Membrane Transport Proteins
PubMed: 33524471
DOI: 10.1016/j.neuint.2021.104980 -
Advances in Protein Chemistry and... 2021PTR2/POT/NPF are a family of primarily proton coupled transporters that belong to the major facilitator super family and are found across most kingdoms of life. They are... (Review)
Review
PTR2/POT/NPF are a family of primarily proton coupled transporters that belong to the major facilitator super family and are found across most kingdoms of life. They are involved in uptake of nutrients, hormones, ions and several orally administered drug molecules. A wealth of structural and functional data is available for this family; the similarity between the protein structural features have been discussed and investigated in detail on several occasions, however there are no reports on the unification of substrate information. In order to fill this gap, we have collected information about substrates across the entire PTR2/POT/NPF family in order to provide key insights into what makes a molecule a substrate and whether there are common features among confirmed substrates. This review will be of particular interest for researchers in the field trying to probe the mechanisms responsible for the different selectivity of these transporters at a molecular resolution, and to design novel substrates.
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Substrate Specificity
PubMed: 33485485
DOI: 10.1016/bs.apcsb.2020.10.002 -
Annals of Allergy, Asthma & Immunology... Dec 2023
Topics: Humans; Calcium-Binding Proteins; Membrane Transport Proteins; Organic Anion Transporters; Hypersensitivity
PubMed: 38044017
DOI: 10.1016/j.anai.2023.09.007 -
Comprehensive Physiology Jun 2021Regulation of the ability of a neurotransmitter [our focus: serotonin, norepinephrine, dopamine, acetylcholine, glycine, and gamma-aminobutyric acid (GABA)] to reach its... (Review)
Review
Regulation of the ability of a neurotransmitter [our focus: serotonin, norepinephrine, dopamine, acetylcholine, glycine, and gamma-aminobutyric acid (GABA)] to reach its receptor targets is regulated in part by controlling the access the neurotransmitter has to receptors. Transporters, located at both the cellular plasma membrane and in subcellular vesicles, carry a myriad of responsibilities that include enabling neurotransmitter release and controlling uptake of neurotransmitter back into a cell or vesicle. Driven largely by electrochemical gradients, these transporters move neurotransmitters. The regulation of the transporters themselves through changes in expression and/or posttranslational modification allows for fine-tuning of this system. Transporters have been best recognized as targets for psychoactive stimulants and remain a mainstay target of primarily central nervous system (CNS) acting drugs for treatment of debilitating diseases such as depression and anxiety. Studies reveal, however, that transporters are found and functional in tissues outside the CNS (gastrointestinal and cardiovascular tissues, for example). The importance of neurotransmitter transporters is underscored with discoveries that dysfunction of transporters can cause life-changing disease. This article provides a high-level review of major classes of both plasma membrane transporters and vesicular transporters. © 2021 American Physiological Society. Compr Physiol 11:2279-2295, 2021.
Topics: Biological Transport; Carrier Proteins; Membrane Transport Proteins; Neurotransmitter Agents; Neurotransmitter Transport Proteins
PubMed: 34190339
DOI: 10.1002/cphy.c200035 -
Current Opinion in Biotechnology Aug 2019Secondary active transporters are fundamental to a myriad of biological processes. They use the electrochemical gradient of one solute to drive transport of another... (Review)
Review
Secondary active transporters are fundamental to a myriad of biological processes. They use the electrochemical gradient of one solute to drive transport of another solute against its concentration gradient. Central to this mechanism is that the transport of one does not occur in the absence of the other. However, like in most of biology, imperfections in the coupling mechanism exist and we argue that these are innocuous and may even be beneficial for the cell. We discuss the energetics and kinetics of alternating-access in secondary transport and focus on the mechanistic aspects of imperfect coupling that give rise to leak pathways. Additionally, inspection of available transporter structures gives valuable insight into coupling mechanics, and we review literature where proteins have been altered to change their coupling efficiency.
Topics: Biological Transport; Kinetics; Membrane Transport Proteins
PubMed: 30502621
DOI: 10.1016/j.copbio.2018.11.005 -
Proteins Oct 2022Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across... (Review)
Review
Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across biomembranes. Accumulated structural and functional knowledge allows for the de novo design of transport proteins with new structures that do not exist in nature. Analysis based on these novel proteins provides new insights into the principles that govern protein assembly, conformational change, and substrate recognition. Here, we review the advances in the de novo design of transporters and channels over recent years and highlight the challenges and opportunities in this field.
Topics: Biological Transport; Carrier Proteins; Membrane Transport Proteins
PubMed: 35305033
DOI: 10.1002/prot.26336