-
Drug Metabolism and Disposition: the... Aug 2023Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to... (Review)
Review
Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to move diverse substrates across the membrane. However, the plasticity of these proteins' ligand binding pockets, which allows them to bind a range of substrates, also poses a challenge for drug development. Here we highlight the structure, function, and transport mechanism of ATP-binding cassette/solute carrier transporters that are related to several diseases and multidrug resistance: ABCB1, ABCC1, ABCG2, SLC19A1, and SLC29A1. SIGNIFICANCE STATEMENT: ATP-binding cassette transporters and solute carriers play vital roles in clinical chemotherapeutic outcomes. This paper describes the current understanding of the structure of five pharmacologically relevant transporters and how they interact with their ligands.
Topics: Membrane Transport Proteins; Cryoelectron Microscopy; Multidrug Resistance-Associated Proteins; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Drug Resistance, Neoplasm
PubMed: 37438132
DOI: 10.1124/dmd.122.001004 -
Nature Metabolism Dec 2023Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased...
Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
Topics: Animals; Membrane Transport Proteins; Biological Transport; Amino Acids; Serine; Colorectal Neoplasms; Mammals
PubMed: 38066114
DOI: 10.1038/s42255-023-00936-2 -
Current Opinion in Nephrology and... Sep 2023We recently localized a new K-Cl cotransporters-3 (KCC3) transporter to the apical membrane of type-B intercalated cells. This gives us an opportunity to revisit the... (Review)
Review
PURPOSE OF REVIEW
We recently localized a new K-Cl cotransporters-3 (KCC3) transporter to the apical membrane of type-B intercalated cells. This gives us an opportunity to revisit the roles of the KCC3 in kidney and integrate the new findings to our current knowledge of the biology of the bicarbonate secreting cells.
RECENT FINDINGS
Here, we review the basic properties of the K-Cl cotransporter with a particular attention to the responsiveness of the transporter to cell swelling. We summarize what is already known about KCC3b and discuss new information gained from our localizing of KCC3a in type-B intercalated cells. We integrate the physiology of KCC3a with the main function of the type-B cell, that is, bicarbonate secretion through the well characterized apical Cl-/HCO3- exchanger and the basolateral Na-HCO3 cotransporter.
SUMMARY
Both KCC3b and KCC3a seem to be needed for maintaining cell volume during enhanced inward cotransport of Na-glucose in proximal tubule and Na-HCO3 in intercalated cells. In addition, apical KCC3a might couple to pendrin function to recycle Cl-, particularly in conditions of low salt diet and therefore low Cl- delivery to the distal tubule. This function is critical in alkalemia, and KCC3a function in the pendrin-expressing cells may contribute to the K+ loss which is observed in alkalemia.
Topics: Animals; Humans; Bicarbonates; Kidney; Symporters; Membrane Transport Proteins; Sulfate Transporters; Mammals; K Cl- Cotransporters
PubMed: 37530088
DOI: 10.1097/MNH.0000000000000911 -
Nature Structural & Molecular Biology Oct 2023Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport...
Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition.
Topics: Anion Exchange Protein 1, Erythrocyte; Bicarbonates; Membrane Transport Proteins; Binding Sites; Protein Domains
PubMed: 37679563
DOI: 10.1038/s41594-023-01085-6 -
Nature Reviews. Drug Discovery Mar 2024
Topics: Humans; Inflammation; Membrane Transport Proteins; Nerve Tissue Proteins
PubMed: 38326471
DOI: 10.1038/d41573-024-00024-4 -
Pharmaceutical Research Nov 2023The oligopeptide/histidine transporters PHT1 and PHT2, two mammalian solute carrier family 15A proteins, mediate the transmembrane transport of histidine and some... (Review)
Review
The oligopeptide/histidine transporters PHT1 and PHT2, two mammalian solute carrier family 15A proteins, mediate the transmembrane transport of histidine and some di/tripeptides via proton gradient. PHT1 and PHT2 are distributed in a variety of tissues but are preferentially expressed in immune cells and localize to the lysosome-related organelles. Studies have reported the relationships between PHT1/PHT2 and immune diseases. PHT1 and PHT2 participate in the regulation of lysosomal homeostasis and lysosome-associated signaling pathways through their transport and nontransport functions, playing important roles in inflammatory diseases. In this review, we summarize recent research on PHT1 and PHT2, aiming to provide reference for their further biological research and as targets for drug design.
Topics: Animals; Biological Transport; Histidine; Mammals; Membrane Transport Proteins; Oligopeptides; Symporters
PubMed: 37610621
DOI: 10.1007/s11095-023-03589-8 -
EMBO Reports Oct 2023Monoamine transporters retrieve serotonin (SERT), dopamine (DAT), and norepinephrine (NET) from the synaptic cleft. Transporter internalization contributes to the...
Monoamine transporters retrieve serotonin (SERT), dopamine (DAT), and norepinephrine (NET) from the synaptic cleft. Transporter internalization contributes to the regulation of their surface expression. Clathrin-mediated endocytosis of plasma membrane proteins requires adaptor protein-2 (AP2), which recruits cargo to the nascent clathrin cage. However, the intracellular portions of monoamine transporters are devoid of a conventional AP2-binding site. Here, we identify a MAD2 (mitotic arrest deficient-2) interaction motif in the C-terminus of SERT, which binds the closed conformation of MAD2 and allows for the recruitment of two additional mitotic spindle assembly checkpoint (SAC) proteins, BubR1 and p31 , and of AP2. We visualize MAD2, BubR1, and p31 in dorsal raphe neurons, and depletion of MAD2 in primary serotonergic rat neurons decreases SERT endocytosis in the soma. Our findings do not only provide mechanistic insights into transporter internalization but also allow for rationalizing why SAC proteins are present in post-mitotic neurons.
Topics: Rats; Animals; Serotonin Plasma Membrane Transport Proteins; Mad2 Proteins; Nuclear Proteins; Cell Cycle Proteins; Adaptor Proteins, Signal Transducing; Endocytosis; Spindle Apparatus; Clathrin
PubMed: 37530743
DOI: 10.15252/embr.202153408 -
Trends in Biochemical Sciences Feb 2024Tripartite ATP-independent periplasmic (TRAP) transporters are nutrient-uptake systems found in bacteria and archaea. These evolutionary divergent transporter systems... (Review)
Review
Tripartite ATP-independent periplasmic (TRAP) transporters are nutrient-uptake systems found in bacteria and archaea. These evolutionary divergent transporter systems couple a substrate-binding protein (SBP) to an elevator-type secondary transporter, which is a first-of-its-kind mechanism of transport. Here, we highlight breakthrough TRAP transporter structures and recent functional data that probe the mechanism of transport. Furthermore, we discuss recent structural and biophysical studies of the ion transporter superfamily (ITS) members and highlight mechanistic principles that are relevant for further exploration of the TRAP transporter system.
Topics: Bacterial Proteins; Membrane Transport Proteins; Carrier Proteins; Bacteria; Biological Transport
PubMed: 38102017
DOI: 10.1016/j.tibs.2023.11.006 -
Disease Models & Mechanisms Nov 2023By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic... (Review)
Review
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
Topics: Humans; Membrane Transport Proteins; Solute Carrier Proteins; Biological Transport; Neoplasms; Cell Physiological Phenomena; Tumor Microenvironment
PubMed: 38037877
DOI: 10.1242/dmm.050404 -
Pharmaceutical Research Nov 2023This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1... (Review)
Review
This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1 (Slc15A4) in the brain. That family transports endogenous di- and tripeptides and peptidomimetics but also a number of drugs. The review focuses on the pioneering work of David E. Smith in the field in identifying the impact of PepT2 at the choroid plexus (the blood-CSF barrier) as well as PepT2 and PhT1 in brain parenchymal cells. It also discusses recent findings and future directions in relation to brain POTs including cellular and subcellular localization, regulatory pathways, transporter structure, species differences and disease states.
Topics: Symporters; Protons; Biological Transport; Membrane Transport Proteins; Oligopeptides; Brain
PubMed: 37308743
DOI: 10.1007/s11095-023-03550-9