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The Journal of General Physiology Jul 2019The lactose permease (LacY) of is the prototype of the major facilitator superfamily, one of the largest families of membrane transport proteins. Structurally, two... (Review)
Review
The lactose permease (LacY) of is the prototype of the major facilitator superfamily, one of the largest families of membrane transport proteins. Structurally, two pseudo-symmetrical six-helix bundles surround a large internal aqueous cavity. Single binding sites for galactoside and H are positioned at the approximate center of LacY halfway through the membrane at the apex of the internal cavity. These features enable LacY to function by an alternating-access mechanism that can catalyze galactoside/H symport in either direction across the cytoplasmic membrane. The H-binding site is fully protonated under physiological conditions, and subsequent sugar binding causes transition of the ternary complex to an occluded intermediate that can open to either side of the membrane. We review the structural and functional evidence that has provided new insight into the mechanism by which LacY achieves active transport against a concentration gradient.
Topics: Binding Sites; Catabolite Repression; Escherichia coli; Escherichia coli Proteins; Lactose; Monosaccharide Transport Proteins; Protons; Symporters
PubMed: 31147449
DOI: 10.1085/jgp.201912377 -
Research in Microbiology 2018Transporters of the RND superfamily are well-known as the major drug efflux pumps of Gram-negative bacteria. However, they are widespread in organisms ranging from... (Review)
Review
Transporters of the RND superfamily are well-known as the major drug efflux pumps of Gram-negative bacteria. However, they are widespread in organisms ranging from Archaea to Eukaryotes, and perform diverse functions. This review gives a brief overview of these diverse members of the superfamily with emphasis on their structure and functions.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Eukaryota; Evolution, Molecular; Humans; Membrane Transport Proteins; Models, Molecular; Multigene Family
PubMed: 29577985
DOI: 10.1016/j.resmic.2018.03.001 -
Cellular and Molecular Life Sciences :... Apr 2015Mitochondrial calcium uptake plays a critical role in various cellular functions. After half a century of extensive studies, the molecular components and important... (Review)
Review
Mitochondrial calcium uptake plays a critical role in various cellular functions. After half a century of extensive studies, the molecular components and important regulators of the mitochondrial calcium uptake complex have been identified. However, the mechanism by which these protein molecules interact with one another and coordinate to regulate calcium passage through mitochondrial membranes remains elusive. Here, we summarize recent progress in the structural and functional characterization of these important protein molecules, which are involved in mitochondrial calcium uptake. In particular, we focus on the current understanding of the molecular mechanism underlying calcium through two mitochondrial membranes. Additionally, we provide a new perspective for future directions in investigation and molecular intervention.
Topics: Antiporters; Calcium; Calcium Channels; Calcium Signaling; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Voltage-Dependent Anion Channels
PubMed: 25548802
DOI: 10.1007/s00018-014-1810-1 -
Proceedings of the National Academy of... Oct 2023Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the...
Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the existing layer of PG is remodeled and PG fragments are released. Enterics such as go to great lengths to internalize and reutilize PG fragments. is estimated to break down one-third of its cell wall, yet only loses ~0 to 5% of meso-diaminopimelic acid, a PG-specific amino acid, per generation. Two transporters were identified early on to possibly be the primary permease that facilitates PG fragment recycling, i) AmpG and ii) the Opp ATP binding cassette transporter in conjunction with a PG-specific periplasmic binding protein, MppA. The contribution of each transporter to PG recycling has been debated. Here, we have found that AmpG and MppA/Opp are differentially regulated by carbon source and growth phase. In addition, MppA/Opp is uniquely capable of high-affinity scavenging of muropeptides from growth media, demonstrating that AmpG and MppA/Opp allow for different strategies of recycling PG fragments. Altogether, this work clarifies environmental contexts under which utilizes distinct permeases for PG recycling and explores how scavenging by MppA/Opp could be beneficial in mixed communities.
Topics: Membrane Transport Proteins; Escherichia coli; Peptidoglycan; Bacterial Proteins; Bacteria; Cell Wall
PubMed: 37871219
DOI: 10.1073/pnas.2308940120 -
Clinical Pharmacology and Therapeutics Nov 2018Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter... (Review)
Review
Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy.Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs; further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches. Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug-drug interactions (DDIs)..
Topics: Animals; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Ligands; Membrane Transport Modulators; Membrane Transport Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Pharmacogenomic Variants; Pharmacokinetics; Phenotype; Protein Conformation; Quantitative Structure-Activity Relationship; Risk Assessment
PubMed: 29981151
DOI: 10.1002/cpt.1174 -
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 -
Molecular Microbiology Apr 2017Transporters are essential players in bacterial growth and survival, since they are key for uptake of nutrients on the one hand, and for defence against endogenous and... (Review)
Review
Transporters are essential players in bacterial growth and survival, since they are key for uptake of nutrients on the one hand, and for defence against endogenous and environmental stresses on the other hand. Remarkably, in addition to their primary role in substrate translocation, it has become clear that some transporters have acquired a secondary function as sensors and information processors in signalling pathways. In this review, we describe recent advances in our understanding of the role of transporters in such signalling cascades, and discuss some of the emergent dynamic behaviour found in hallmark examples. A particular focus is placed on new insights into mechanistic details of information transfer between transporters and regulatory proteins. Quantitative considerations reveal that these signalling complexes can implement a remarkable diversity of regulatory logic functions, where the transporter can act as activity switch, as positive or negative reporter of transport flux, or as a signalling hub for the integration of multiple inputs. Such a dual use of transport proteins not only enables efficient substrate translocation but is also an elegant strategy to integrate important information about the cell's external conditions with its current physiological state.
Topics: Bacterial Proteins; Carrier Proteins; Membrane Transport Proteins; Signal Transduction
PubMed: 28152228
DOI: 10.1111/mmi.13633 -
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 -
Biochemical Society Transactions Feb 2019Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in... (Review)
Review
Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in our understanding of how oligomerisation affects these key transporter features, with emphasis on a few groups of transporters, including the nucleobase ascorbate transporters, neurotransmitter sodium symporters and major facilitator superfamily members.
Topics: Ascorbic Acid; Membrane Transport Proteins; Neurotransmitter Agents; Polymerization
PubMed: 30578344
DOI: 10.1042/BST20180316 -
Biochimica Et Biophysica Acta Aug 2014The membrane insertases YidC-Oxa1-Alb3 provide a simple cellular system that catalyzes the transmembrane topology of newly synthesized membrane proteins. The insertases... (Review)
Review
The membrane insertases YidC-Oxa1-Alb3 provide a simple cellular system that catalyzes the transmembrane topology of newly synthesized membrane proteins. The insertases are composed of a single protein with 5 to 6 transmembrane (TM) helices that contact hydrophobic segments of the substrate proteins. Since YidC also cooperates with the Sec translocase it is widely involved in the assembly of many different membrane proteins including proteins that obtain complex membrane topologies. Homologues found in mitochondria (Oxa1) and thylakoids (Alb3) point to a common evolutionary origin and also demonstrate the general importance of this cellular process. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Adenosine Triphosphatases; Bacterial Proteins; Electron Transport Complex IV; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Nuclear Proteins; Protein Folding; Protein Transport; SEC Translocation Channels; SecA Proteins; Thylakoid Membrane Proteins
PubMed: 24418623
DOI: 10.1016/j.bbamcr.2013.12.022