17 results on '"Heemels MT"'
Search Results
2. Neurodegenerative diseases.
- Author
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Heemels MT
- Subjects
- Aging drug effects, Aging metabolism, Alzheimer Disease metabolism, Alzheimer Disease therapy, Amyotrophic Lateral Sclerosis pathology, Humans, Parkinson Disease metabolism, Parkinson Disease pathology, Prions chemistry, Prions metabolism, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Neurodegenerative Diseases therapy
- Published
- 2016
- Full Text
- View/download PDF
3. Lipids in health and disease.
- Author
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Finkelstein J, Heemels MT, Shadan S, and Weiss U
- Subjects
- Adipose Tissue metabolism, Fatty Acids, Omega-3 metabolism, Fatty Acids, Omega-3 therapeutic use, Fatty Liver metabolism, Humans, Non-alcoholic Fatty Liver Disease, Sphingolipids metabolism, Health, Lipid Metabolism, Metabolic Diseases metabolism
- Published
- 2014
- Full Text
- View/download PDF
4. Frontiers in biology.
- Author
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Cesari F, Chou IH, Eggleston AK, Heemels MT, Marte B, and Weiss U
- Subjects
- Aging metabolism, Animals, Child, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive pathology, Child Development Disorders, Pervasive physiopathology, Fanconi Anemia Complementation Group Proteins metabolism, Humans, Immune System metabolism, Mice, Morphogenesis, TOR Serine-Threonine Kinases metabolism, Biology
- Published
- 2013
- Full Text
- View/download PDF
5. Metabolism and disease.
- Author
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Finkelstein J, Gray N, Heemels MT, Marte B, and Nath D
- Subjects
- Circadian Rhythm, Humans, Mitochondria physiology, Neoplasms metabolism, Neoplasms pathology, Metabolic Diseases pathology
- Published
- 2012
- Full Text
- View/download PDF
6. Frontiers in biology.
- Author
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Eccleston A, Eggleston A, Heemels MT, Marte B, and Weiss U
- Subjects
- Animals, Bone and Bones metabolism, Clonal Evolution, DNA Damage, Embryonic Stem Cells cytology, Humans, Induced Pluripotent Stem Cells cytology, Inflammasomes immunology, Inflammasomes metabolism, Metabolism, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology, Neoplasms therapy, Biological Science Disciplines
- Published
- 2012
- Full Text
- View/download PDF
7. Ageing.
- Author
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Heemels MT
- Subjects
- Animals, Humans, Nutritional Physiological Phenomena, Aging
- Published
- 2010
- Full Text
- View/download PDF
8. A remarkable 'death on the rocks'
- Author
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Heemels MT
- Published
- 1999
- Full Text
- View/download PDF
9. Generation, translocation, and presentation of MHC class I-restricted peptides.
- Author
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Heemels MT and Ploegh H
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Antigen Presentation, Biological Transport, Active, Cysteine Endopeptidases metabolism, Histocompatibility Antigens Class I biosynthesis, Histocompatibility Antigens Class I chemistry, Humans, Molecular Chaperones metabolism, Molecular Structure, Multienzyme Complexes metabolism, Peptide Biosynthesis, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Proteins metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Viral Matrix Proteins metabolism, Histocompatibility Antigens Class I metabolism, Peptides immunology, Peptides metabolism
- Abstract
The T lymphocytes of the vertebrate immune system look for changes that take place within the organism by examining a display of peptides at the cell surface. These peptides are presented by the products of the major histocompatibility complex (MHC). MHC class I products present peptides derived by proteolysis of cytosolic proteins by the multicatalytic protease, the proteasome. These peptides are translocated from the cytosol into the endoplasmic reticulum by a dedicated peptide transporter, the transporter associated with antigen presentation (TAP). TAP consists of two subunits, and translocates peptides that are approximately 8-12 residues in length. The COOH terminal residue of the peptide is a major determinant in the specificity of translocation. Following translocation, peptides bind to MHC class I molecules, which depend on the peptide ligand as well as on interactions with chaperonins for proper folding. These complexes then egress from the ER and are transported to their final destination, the cell surface.
- Published
- 1995
- Full Text
- View/download PDF
10. Substrate specificity of allelic variants of the TAP peptide transporter.
- Author
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Heemels MT and Ploegh HL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3, ATP-Binding Cassette Transporters genetics, Alleles, Amino Acid Sequence, Animals, Binding, Competitive, Biological Transport, Liver metabolism, Molecular Sequence Data, Rats, Rats, Inbred F344, Rats, Inbred Lew, Sequence Analysis, Substrate Specificity, ATP-Binding Cassette Transporters metabolism, Microsomes metabolism
- Abstract
The transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the lumen of the endoplasmic reticulum (ER). An important determinant for the specificity of translocation is the identity of the C-terminal residue of the peptide substrate. In the rat, a suitable C terminus is necessary but not always sufficient for a peptide to be selected for translocation. Here we show that sequence constraints within a peptide of optimal length (9 residues) may interfere with transport; that the transporter selectively translocates shorter derivatives of a 16-mer peptide rather than the 16-mer itself; and that the transporter cimb allele, which is most selective in the C termini it will tolerate, is more relaxed in peptide length preference than is the clma variant.
- Published
- 1994
- Full Text
- View/download PDF
11. Peptide length and sequence specificity of the mouse TAP1/TAP2 translocator.
- Author
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Schumacher TN, Kantesaria DV, Heemels MT, Ashton-Rickardt PG, Shepherd JC, Fruh K, Yang Y, Peterson PA, Tonegawa S, and Ploegh HL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3, Adenosine Triphosphate metabolism, Amino Acid Sequence, Animals, Binding, Competitive, Biological Transport, Female, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Peptides chemistry, Peptides immunology, Temperature, ATP-Binding Cassette Transporters, Carrier Proteins metabolism, Histocompatibility Antigens Class II metabolism, Peptides metabolism
- Abstract
The transporter associated with antigen processing (TAP) delivers peptides to the lumen of the endoplasmic reticulum in an adenosine triphosphate (ATP) dependent fashion for presentation by major histocompatibility complex class I molecules. We show that the mouse TAP translocator (H-2b haplotype) selects peptides based on a minimal size of nine residues, and on the presence of a hydrophobic COOH-terminal amino acid. The preponderance of COOH-terminal hydrophobic amino acids in peptides capable of binding to mouse class I molecules thus fits remarkably well with the specificity of the TAP translocator. In addition to transport in the lumenal direction, efflux of peptide in the cytosolic direction is observed in an ATP- and temperature-dependent manner. By maintaining a low peptide concentration at the site of class I assembly, this efflux mechanism may ensure that class I molecules are loaded preferentially with high affinity peptides.
- Published
- 1994
- Full Text
- View/download PDF
12. Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas.
- Author
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Cromme FV, Airey J, Heemels MT, Ploegh HL, Keating PJ, Stern PL, Meijer CJ, and Walboomers JM
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, Antibody Specificity, Biological Transport, Carrier Proteins genetics, Female, HLA Antigens genetics, HLA Antigens immunology, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class II genetics, Humans, Immune Sera, ATP-Binding Cassette Transporters, Carrier Proteins metabolism, HLA Antigens biosynthesis, Histocompatibility Antigens Class II metabolism, Uterine Cervical Neoplasms immunology
- Abstract
Malignant tumor cells can escape CD8+ cytotoxic T cell killing by downregulating class I major histocompatibility complex (MHC) expression. Stable class I MHC surface expression requires loading of the heavy chain/light chain dimer with antigenic peptide, which is delivered to class I MHC molecules in the endoplasmic reticulum by the presumed peptide transporter, encoded by the transporter associated with antigen presentation (TAP) 1 and 2 genes. We have investigated whether loss of class I MHC expression frequently observed in different cancers could result from interference with TAP function. A polyclonal antiserum, raised against a bacterial glutathione S-transferase/human TAP-1 fusion protein, was used for the immunohistochemical analysis of TAP-1 expression in 76 cervical carcinomas. Results showed loss of TAP-1 expression in neoplastic cells in 37 out of 76 carcinomas. Immunohistochemical double staining procedures in combination with HLA-specific antibodies revealed congruent loss at the single cell level of TAP-1 and HLA-A/B expression in 28 out of 37 carcinomas. The remaining samples expressed HLA(-A) in the absence of TAP-1 (n = 6) or showed loss of HLA(-A/B) while TAP-1 was expressed (n = 3). These data strongly indicate that inhibition of peptide transport by downregulation of TAP-1 is a potential strategy of malignant cells to evade immune surveillance.
- Published
- 1994
- Full Text
- View/download PDF
13. Peptide translocation by variants of the transporter associated with antigen processing.
- Author
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Heemels MT, Schumacher TN, Wonigeit K, and Ploegh HL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3, Alleles, Amino Acid Sequence, Animals, Biological Transport physiology, Carrier Proteins genetics, Histocompatibility Antigens Class I physiology, Histocompatibility Antigens Class II genetics, In Vitro Techniques, Microsomes, Liver metabolism, Molecular Sequence Data, Rats, Rats, Inbred BN, Rats, Inbred Lew, Rats, Inbred SHR, Substrate Specificity, ATP-Binding Cassette Transporters, Antigen Presentation physiology, Carrier Proteins physiology, Histocompatibility Antigens Class II physiology, Oligopeptides metabolism
- Abstract
Major histocompatibility complex (MHC) class I molecules associate with peptides that are delivered from the cytosol to the lumen of the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Liver microsomes of SHR and Lewis rats, which express different alleles of TAP (cim(b) and cim(a), respectively), accumulate different sets of peptides. Use of MHC congenic rats assigned this difference to the MHC, independent of the class I products expressed. Both the cim(a) and cim(b) TAP complexes translocate peptides with a hydrophobic carboxyl terminus, but translocation of peptides with a carboxyl-terminal His, Lys, or Arg residue is unique to cim(a). Thus, the specificity of the TAP peptide translocator restricts the peptides available for antigen presentation.
- Published
- 1993
- Full Text
- View/download PDF
14. Antigen presentation: untapped peptides.
- Author
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Heemels MT and Ploegh H
- Published
- 1993
- Full Text
- View/download PDF
15. Synthetic peptide libraries in the determination of T cell epitopes and peptide binding specificity of class I molecules.
- Author
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Schumacher TN, Van Bleek GM, Heemels MT, Deres K, Li KW, Imarai M, Vernie LN, Nathenson SG, and Ploegh HL
- Subjects
- Amino Acid Sequence, Animals, Antigen-Antibody Reactions, Cells, Cultured, Dose-Response Relationship, Immunologic, H-2 Antigens isolation & purification, Immunosuppression Therapy, Mice, Molecular Sequence Data, Nucleocapsid Proteins, Polymorphism, Genetic, T-Lymphocytes, Cytotoxic immunology, Viral Core Proteins immunology, Antibody Specificity immunology, Epitopes immunology, H-2 Antigens immunology, Nucleoproteins, T-Lymphocytes immunology
- Abstract
Major histocompatibility complex (MHC) class I molecules combine with short peptides of defined length and sequence. Here we describe an approach that may be used in the analysis of peptide preference of different allelic MHC class I molecules, and in the determination of T cell epitopes. We produced synthetic "peptide libraries" of limited complexity by standard peptide chemistry. Using these peptide mixtures we show that H-2 Kb molecules can accommodate both 8- and 9-residue peptides, whereas Db molecules are unable to combine with peptides shorter than 9 amino acids present in these libraries. When these peptide mixtures are used to provide "fingerprints" of Db molecules and mutants thereof, both loss and gain of the ability to combine with certain peptides is observed. For the Kbm1 mutant a strong influence of amino acid substitutions in class I molecules on the peptides selected is observed. In these synthetic peptide mixtures, the presence of a specific T cell epitope, known to be represented once, can be detected. This approach may be extended to the identification of new T cell epitopes from larger peptide libraries.
- Published
- 1992
- Full Text
- View/download PDF
16. Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro.
- Author
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Schumacher TN, Heemels MT, Neefjes JJ, Kast WM, Melief CJ, and Ploegh HL
- Subjects
- Animals, Cell Line, Cell Membrane immunology, Electrophoresis, Polyacrylamide Gel, H-2 Antigens immunology, Histocompatibility Antigens Class I isolation & purification, Immunoenzyme Techniques, Mice, Peptides chemical synthesis, Protein Binding, Histocompatibility Antigens Class I immunology
- Abstract
MHC class I molecules devoid of peptide are expressed on the cell surface of the mouse mutant lymphoma cell line RMA-S upon culture at reduced temperature. Empty class I molecules are thermolabile at the cell surface and in detergent lysates, but can be stabilized by the addition of presentable peptide; peptide binding appears to be a rapid process. Furthermore, class I molecules on the surface of RMA-S (H-2b haplotype) cells cultured at 26 degrees C can efficiently and specifically bind iodinated peptide presented by H-2Kb. Binding of iodinated peptide is also observed at a lower level for nonmutant cells (RMA) cultured at 26 degrees C. These experiments underscore the role for peptide in maintenance of the structure of class I molecules and, more importantly, provide two assay systems to study the interactions of peptides with MHC class I molecules independent of the availability of T cells that recognize a particular peptide-MHC class I complex.
- Published
- 1990
- Full Text
- View/download PDF
17. Empty MHC class I molecules come out in the cold.
- Author
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Ljunggren HG, Stam NJ, Ohlén C, Neefjes JJ, Höglund P, Heemels MT, Bastin J, Schumacher TN, Townsend A, and Kärre K
- Subjects
- Animals, Antigen-Presenting Cells immunology, Biological Transport, Cell Membrane immunology, H-2 Antigens immunology, Lymphoma, Macromolecular Substances, Mice, Mutation, Protein Binding, Protein Conformation, Protein Processing, Post-Translational, T-Lymphocytes, Cytotoxic immunology, Tumor Cells, Cultured, beta 2-Microglobulin metabolism, Cold Temperature, H-2 Antigens metabolism
- Abstract
Major histocompatibility complex (MHC) class I molecules present antigen by transporting peptides from intracellularly degraded proteins to the cell surface for scrutiny by cytotoxic T cells. Recent work suggests that peptide binding may be required for efficient assembly and intracellular transport of MHC class I molecules, but it is not clear whether class I molecules can ever assemble in the absence of peptide. We report here that culture of the murine lymphoma mutant cell line RMA-S at reduced temperature (19-33 degrees C) promotes assembly, and results in a high level of cell surface expression of H-2/beta 2-microglobulin complexes that do not present endogenous antigens, and are labile at 37 degrees C. They can be stabilized at 37 degrees C by exposure to specific peptides known to interact with H-2Kb or Db. Our findings suggest that, in the absence of peptides, class I molecules can assemble but are unstable at body temperature. The induction of such molecules at reduced temperature opens new ways to analyse the nature of MHC class I peptide interactions at the cell surface.
- Published
- 1990
- Full Text
- View/download PDF
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