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Biochimica Et Biophysica Acta Dec 1999The transporter associated with antigen processing (TAP) is essential for peptide loading onto major histocompatibility complex (MHC) class I molecules by translocating... (Review)
Review
The transporter associated with antigen processing (TAP) is essential for peptide loading onto major histocompatibility complex (MHC) class I molecules by translocating peptides into the endoplasmic reticulum. The MHC-encoded ABC transporter works in concert with the proteasome and MHC class I molecules for the antigen presentation on the cell surface for T cell recognition. TAP forms a heterodimer where each subunit consists of a hydrophilic nucleotide binding domain and a hydrophobic transmembrane domain. The transport mechanism is a multistep process composed of an ATP-independent peptide association step which induces a structural reorganization of the transport complex that may trigger the ATP-driven transport of the peptide into the endoplasmic reticulum lumen. By using combinatorial peptide libraries, the substrate selectivity and the recognition principle of TAP have been elucidated. TAP maximizes the degree of substrate diversity in combination with high substrate affinity. This ABC transporter is also unique as it is closely associated with chaperone-like proteins involved in bonding of the substrate onto MHC molecules. Most interestingly, virus-infected and malignant cells have developed strategies to escape immune surveillance by affecting TAP expression or function.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP Binding Cassette Transporter, Subfamily B, Member 3; ATP-Binding Cassette Transporters; Adenosine Triphosphate; Animals; Antigen-Presenting Cells; Antiporters; Biological Transport; Cell Membrane; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I; Humans; Immunoglobulins; Intracellular Membranes; Major Histocompatibility Complex; Membrane Transport Proteins; Models, Molecular; Peptide Library; Peptides; Substrate Specificity; T-Lymphocytes, Cytotoxic
PubMed: 10581370
DOI: 10.1016/s0005-2736(99)00171-6 -
Nihon Yakurigaku Zasshi. Folia... Apr 2013
Review
Topics: Animals; Cell Membrane; Cell Membrane Permeability; Cell-Penetrating Peptides; Humans; Membrane Transport Proteins
PubMed: 23575428
DOI: 10.1254/fpj.141.220 -
FASEB Journal : Official Publication of... Dec 2000Sequence-related vesicular acetylcholine transporter (VAChT) and vesicular monoamine transporter (VMAT) transport neurotransmitter substrates into secretory vesicles.... (Review)
Review
Sequence-related vesicular acetylcholine transporter (VAChT) and vesicular monoamine transporter (VMAT) transport neurotransmitter substrates into secretory vesicles. This review seeks to identify shared and differentiated aspects of the transport mechanisms. VAChT and VMAT exchange two protons per substrate molecule with very similar initial velocity kinetics and pH dependencies. However, vesicular gradients of ACh in vivo are much smaller than the driving force for uptake and vesicular gradients of monoamines, suggesting the existence of a regulatory mechanism in ACh storage not found in monoamine storage. The importance of microscopic rather than macroscopic kinetics in structure-function analysis is described. Transporter regions affecting binding or translocation of substrates, inhibitors, and protons have been found with photoaffinity labeling, chimeras, and single-site mutations. VAChT and VMAT exhibit partial structural and mechanistic homology with lactose permease, which belongs to the same sequence-defined superfamily, despite opposite directions of substrate transport. The vesicular transporters translocate the first proton using homologous aspartates in putative transmembrane domain X (ten), but they translocate the second proton using unknown residues that might not be conserved between them. Comparative analysis of the VAChT and VMAT transport mechanisms will aid understanding of regulation in neurotransmitter storage.
Topics: Acetylcholine; Amino Acid Sequence; Biogenic Monoamines; Biological Transport; Carrier Proteins; Membrane Glycoproteins; Membrane Transport Proteins; Models, Chemical; Molecular Sequence Data; Neuropeptides; Thermodynamics; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins; Vesicular Transport Proteins
PubMed: 11099460
DOI: 10.1096/fj.00-0203rev -
International Review of Cytology 1992
Review
Topics: Adenosine Triphosphate; Amino Acids; Bacteria; Biological Transport; Carrier Proteins; Maltose; Membrane Transport Proteins; Peptides; Signal Transduction
PubMed: 1428673
DOI: 10.1016/s0074-7696(08)62673-x -
Annual Review of Nutrition 1996Even though the existence of a transport process for intact peptides in the brush border membrane of intestinal and renal absorptive epithelial cells has been known for... (Review)
Review
Even though the existence of a transport process for intact peptides in the brush border membrane of intestinal and renal absorptive epithelial cells has been known for almost three decades, it is only recently that the molecular nature of the proteins responsible for the transport process has been elucidated. Two peptide transporters, PEPT 1 and PEPT 2, have been cloned. The cloned transporters catalyze active transport of intact di- and tripeptides and utilize a transmembrane electrochemical H+ gradient as the driving force. The characteristic of H+ coupling makes PEPT 1 and PEPT 2 unique among the transporters thus far identified in mammalian cells. In addition, the peptide transporters have immediate pharmacologic relevance because a number of peptide-like drugs are recognized as substrates by these transporters. Recently, cultured cell lines of intestinal and renal origin that express PEPT 1 and PEPT 2 have been identified. These cell lines are likely to facilitate studies on the regulatory aspects of the peptide transporters.
Topics: Animals; Biological Transport, Active; Carrier Proteins; Cloning, Molecular; Humans; Intestinal Mucosa; Kidney; Peptide Transporter 1; Symporters
PubMed: 8839921
DOI: 10.1146/annurev.nu.16.070196.000531 -
Biochimica Et Biophysica Acta Mar 2015ABC transporters ubiquitously found in all kingdoms of life move a broad range of solutes across membranes. Crystal structures of four distinct types of ABC transport... (Review)
Review
BACKGROUND
ABC transporters ubiquitously found in all kingdoms of life move a broad range of solutes across membranes. Crystal structures of four distinct types of ABC transport systems have been solved, shedding light on different conformational states within the transport process. Briefly, ATP-dependent flipping between inward- and outward-facing conformations allows directional transport of various solutes.
SCOPE OF REVIEW
The heterodimeric transporter associated with antigen processing TAP1/2 (ABCB2/3) is a crucial element of the adaptive immune system. The ABC transport complex shuttles proteasomal degradation products into the endoplasmic reticulum. These antigenic peptides are loaded onto major histocompatibility complex class I molecules and presented on the cell surface. We detail the functional modules of TAP, its ATPase and transport cycle, and its interaction with and modulation by other cellular components. In particular, we emphasize how viral factors inhibit TAP activity and thereby prevent detection of the infected host cell by cytotoxic T-cells.
MAJOR CONCLUSIONS
Merging functional details on TAP with structural insights from related ABC transporters refines the understanding of solute transport. Although human ABC transporters are extremely diverse, they still may employ conceptually related transport mechanisms. Appropriately, we delineate a working model of the transport cycle and how viral factors arrest TAP in distinct conformations.
GENERAL SIGNIFICANCE
Deciphering the transport cycle of human ABC proteins is the major issue in the field. The defined peptidic substrate, various inhibitory viral factors, and its role in adaptive immunity provide unique tools for the investigation of TAP, making it an ideal model system for ABC transporters in general. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
Topics: ATP-Binding Cassette Transporters; Adaptive Immunity; Animals; Antigen Presentation; Biological Transport; Endoplasmic Reticulum; Humans; Models, Molecular; Peptides; Protein Conformation
PubMed: 24923865
DOI: 10.1016/j.bbagen.2014.05.022 -
Biomolecules Mar 2023The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters....
The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters. Molecular modeling and computer-assisted docking of peptide ligands revealed that the size and structure of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analysis of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters has been carried out. The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides, for which no biological activity has been established. This indicates an important possible role which LAT and PEPT family transporters may play in a variety of biological activities of the 26 biologically active peptides under investigation in this study. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp or Glu amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide are found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters. The data obtained lead to new prospects for further study of the mechanisms of transport of USP-based drugs into the cell and design of new antitumor drugs.
Topics: Feasibility Studies; Amino Acids; Peptides; Membrane Transport Proteins; Biological Transport
PubMed: 36979488
DOI: 10.3390/biom13030552 -
Ciba Foundation Symposium 1971
Topics: Amino Acids; Biological Transport; Cell Membrane; Cell Membrane Permeability; Escherichia coli; Membrane Transport Proteins; Oligopeptides; Peptides
PubMed: 4949893
DOI: 10.1002/9780470719879.ch2 -
Cancer Research Mar 2001Small hydrophobic peptides were studied as possible substrates of the multidrug resistance protein (MRP)-1 (ABCC1) transmembrane transporter molecule. As observed...
Small hydrophobic peptides were studied as possible substrates of the multidrug resistance protein (MRP)-1 (ABCC1) transmembrane transporter molecule. As observed earlier for P-glycoprotein- (Pgp; ABCB1) overexpressing cells, MRP1-overexpressing cells, including cells stably transfected with the MRP1 cDNA, showed distinct resistance to the cytotoxic peptide N-acetyl-Leu-Leu-norleucinal (ALLN). Resistance to this peptide and another toxic peptide derivative, which is based on a Thr-His-Thr-Nle-Glu-Gly backbone conjugated to butyl and benzyl groups (4A6), could be reversed by MRP1 inhibitors. The reduced toxicity of 4A6 in MRP1-overexpressing cells was found to be associated with lower accumulation of a fluorescein-labeled derivative of this peptide. Glutathione (GSH) depletion had a clear effect on resistance to ALLN but hardly affected 4A6 resistance. In a limited structure-activity study using peptides that are analogous to 4A6, MRP1-overexpressing cells were found to be resistant to these peptides as well. Remarkably, when selecting A2780 ovarian cancer cells for resistance to ALLN, even in the absence of Pgp blockers, resulting cell lines had up-regulated MRP1, rather than any of the other currently known multidrug resistance transporter molecules including Pgp, MRP2 (ABCC2), MRP3 (ABCC3), MRP5 (ABCCS), and the breast cancer resistance protein ABCG2. ALLN-resistant, MRP1-overexpressing cells were found to be cross-resistant to 4A6 and the classical multidrug resistance drugs doxorubicin, vincristine, and etoposide. This establishes MRP1 as a transporter for small hydrophobic peptides. More extensive structure-activity relationship studies should allow the identification of clinically useful peptide antagonists of MRP1.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Biological Transport; Buthionine Sulfoximine; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; HL-60 Cells; Humans; Leupeptins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Oligopeptides; Tumor Cells, Cultured; Valinomycin
PubMed: 11289130
DOI: No ID Found -
Veterinary Pathology Mar 2011Membrane transport processes, at both the plasma membranes and intracellular membranes, play critical roles in renal function and are a determining factor in the... (Review)
Review
Membrane transport processes, at both the plasma membranes and intracellular membranes, play critical roles in renal function and are a determining factor in the susceptibility of renal epithelial cells to blood-borne drugs and toxic chemicals. Proximal tubular epithelial cells possess a large array of transport proteins for organic anions, organic cations, and peptides on both basolateral and brush-border plasma membranes. Although these transporters function in excretion of waste products and reabsorption of nutrients, they also play a role in the susceptibility of the kidneys to drugs and other toxicants in the blood. The proximal tubules are typically the primary target cells because they are the first epithelial cell population exposed to such chemicals in either the renal plasma or glomerular filtrate and because of their large array of membrane transporters. Besides transport across the basolateral and brush-border plasma membranes, transport across intracellular membranes such as the mitochondrial inner membrane is a critical determinant of metabolite distribution. To illustrate the function of these transporters, carrier-mediated processes for transport of the tripeptide and antioxidant glutathione across the basolateral, brush-border, and mitochondrial inner membranes of the renal proximal tubule are reviewed. Studies are summarized that have identified the involvement of specific carrier proteins and characterized the role of these transporters in glutathione metabolism and turnover, susceptibility of the proximal tubules to oxidative and other stresses, and modulation in disease and other pathological processes.
Topics: Animals; Biological Transport; Cell Membrane; Glutathione; Homeostasis; Intracellular Membranes; Ion Pumps; Kidney Tubules, Proximal; Oxidative Stress
PubMed: 20656901
DOI: 10.1177/0300985810375811