Disease relevance of TAP1

• Cell cycle-dependent expression of TAP1, TAP2, and HLA-B27 messenger RNAs in a human breast cancer cell line [1].
• Mutations at cMS of beta2m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002) [2].
• TAP1, TAP2, and HLA Class I antigen expression was more frequently (P < 0.05) down-regulated in metastatic than in primary melanoma lesions and in nevi [3].
• To elucidate the ATP binding properties of these proteins in vitro, we expressed the hydrophilic C-terminal part of human transporter associated with antigen processing (TAP1) (nucleotide binding domain (NBD)-TAP1, amino acids 452-748) and TAP2 (NBD-TAP2, amino acids 399-686) fused to a His6 tag in Escherichia coli [4].
• Analysis of MHC encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis [5].

High impact information on TAP1

• A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer [6].
• Even though the R659Q protein is expressed, these cells act as if they were TAP deficient by peptide binding and antigen presentation studies, which are restored after transfection of a functional TAP1 allele [6].
• In this study, we evaluated 79 human solid tumours and cell lines for genetic abnormalities in TAP1 that might have led to an acquired loss of antigen presenting ability [6].
• Membranous nephropathy and a TAP1 gene polymorphism [7].
• These peptides are translocated in an ATP-dependent fashion into the lumen of the endoplasmic reticulum (ER) for binding to class I molecules by means of the MHC-encoded transporters associated with antigen processing, TAP1 and TAP2 [8].

Chemical compound and disease context of TAP1

• After expression in TAP-deficient human fibroblasts, cysteine-less TAP1 and TAP2 are functional with respect to adenosine triphosphate (ATP)-dependent peptide transport and inhibition by ICP47 from herpes simplex virus [9].
• Processing of HIV-1 envelope glycoprotein for class I-restricted recognition: dependence on TAP1/2 and mechanisms for cytosolic localization [10].
• 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 [11].
• The flash-induced Fourier transform infrared (FTIR) difference spectrum of the oxygen-evolving Mn cluster upon S1-to-S2 transition (S2/S1 spectrum) was measured using photosystem II (PS II) core complexes of Synechocystis 6803 in which tyrosine residues were specifically labeled with 13C at the ring-4 position [12].

Biological context of TAP1

• We now report the initial characterization of the bidirectional promoter for the human transporter associated with antigen processing 1 (TAP1) and low molecular mass polypeptide 2 (LMP2) genes [13].
• The action of two genetic process is required to account for this phenomenon: a recombinational hotspot operating between TAP1 and TAP2, to eliminate disequilibrium between these loci, and at the same time selection operating on particular combinations of alleles across the DR-DP region, to create disequilibrium in the favored haplotypes [14].
• Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10 [15].
• We have addressed this question by analyzing three human melanoma cell lines with distinct phenotypes of LMP2 and TAP1 expression [16].
• Transfection of single TAP genes to T2 or .174 cells, whether TAP1 or TAP2, did not markedly affect NK cell susceptibility [17].

Anatomical context of TAP1

• Downregulation of TAP1 by IL-10 hampers the transport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptide transporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cell surface [15].
• The peptides are generated mainly by the proteasome and are transported to the endoplasmic reticulum by a peptide transport pump consisting of two subunits, TAP1 and TAP2 [18].
• However, restoration of Ag processing and presentation to CD8+ cytotoxic T cells can be achieved by transfecting TAP1 and TAP2 genes into the T2 and .174 cells, or the TAP1 gene into .134 cells [17].
• The TAP heterodimer (TAP1-TAP2) introduces the final component of the MHC class I molecule by translocating peptides, predominately generated by the proteasome, from the cytosol into the ER where they can bind dimers of beta 2M and the MHC class I heavy chain [19].
• Resistance to natural killer cell lysis conferred by TAP1/2 genes in human antigen-processing mutant cells [17].

Associations of TAP1 with chemical compounds

• Since neither purified nor induced ICP47 inhibited photocrosslinking of 8-azido-ATP to TAP1 and TAP2 it seems that ICP47 does not prevent ATP from binding to TAP [20].
• Mutation of the leucine or glycine (LSGGQ) in TAP1 fully abolished peptide transport [21].
• Instead of a glutamate, proposed to act as a general base, TAP1 contains an aspartate and a glutamine instead of the conserved histidine, which has been suggested to act as the linchpin [22].
• Photoaffinity labeling of NBD-TAP1 with the ATP analogues 8-azido-[gamma-32P]ATP and 3'-O-[(4-azido-3,5-[125I]diiodo-2-hydroxybenzoyl)-beta-alanyl]-ATP was specific [4].
• NBD-TAP1 bound to C-8-ATP-agarose and was specifically eluted with ATP or EDTA [4].

Physical interactions of TAP1

• All mutant TAP1 proteins were localized in the ER and were capable of forming complexes with the TAP2 subunit [23].
• However, the TAP1 mutants analyzed transported peptides with different efficiencies and displayed a heterogeneous MHC class I surface expression pattern which was directly associated with their susceptibility to cytotoxic T lymphocyte-mediated lysis [23].
• The dimerization of some vancomycin group antibiotics is strongly exothermic (-36 to -51 kJ.mol-1) and is promoted by a factor of 50-100 by a disaccharide attached to ring 4 (in vancomycin and eremomycin) and by a factor of ca. 1000 by an amino-sugar attached to the benzylic position of ring 6 in eremomycin [24].

Regulatory relationships of TAP1

• This pathway may depend on a transporter (PSF1) to mediate entry of the cytosolic peptides into a pre-Golgi compartment where they bind to class I heavy chains and promote their stable assembly with beta 2-microglobulin [25].
• By confocal immunofluorescence microscopy, TAP1 when expressed alone or with TAP2 is largely, if not exclusively, localized to the endoplasmic reticulum [26].
• p53 induces TAP1 and enhances the transport of MHC class I peptides [27].
• IFN-gamma up-regulates the expression of MHC-class-I antigens and TAP1 both in control and in TAP1-transfected RCC cells to a similar level [28].
• Allelic variation at the TAP 1 locus influences disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis [29].

Other interactions of TAP1

• The genetic defect in .174 has been localized to a large deletion in the class II region of the major histocompatibility complex, within which two genes (RING4 and RING11) have been identified that code for 'ABC' (ATP-binding cassette) transporters [30].
• TAP1 and P-gp share a significant degree of homology among their transmembrane domains, which are thought to be the primary determinants of substrate specificity, and both can apparently mediate the translocation of peptides [31].
• The forces producing the patterns of disequilibrium observed here have implications for the mapping of train loci and disease genes: markers of TAP1, for example, would give a false impression as to the influence of DPB1 on a trait known to be associated with DQB1 [14].
• The regulatory elements within the LMP2/TAP1 promoter and the transcription factors that bind these elements have been defined [16].
• A gamma-activating sequence (GAS) in the TAP1 promoter is necessary for the rapid induction by IFN-gamma [32].

Analytical, diagnostic and therapeutic context of TAP1

• Comparing the UK and Polish control groups, we observed a difference in TAP1 [5].
• Immunoprecipitation and immobilized metal affinity chromatography revealed complex formation between TAP1 and TAP2 [33].
• Therefore, using RT-PCR, we have investigated the HLA class I transcriptional expression in a locus-specific manner, along with HLA-associated accessory molecules beta2-microglobulin and transporter-associated antigen processing molecule (TAP1) [34].
• To determine a gene associated with MHC class I surface expression, the expressions of LMP2/7 and TAP1/2 including MHC I gene were analyzed in ten human gastric cancer cell lines, using RT-PCR and Northern blot analysis [35].
• Analyses with polymerase chain reaction (PCR) based restrictions were used to identify the polymorphisms of the TAP1 and TAP2 genes, which were mapped on chromosome 6 [36].

References