MHC class l/β2-microglobulin complexes associate with TAP transporters before peptide binding

Ortmann, Bodo; Androlewicz, Matthew J.; Cresswell, Peter

doi:10.1038/368864a0

Cited by 351 publications

(221 citation statements)

References 27 publications

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“…The footprint of each domain in the ring (22 ϫ 56 Å) would correspond well with the space required for 7-8 transmembrane helices and short connecting loops (18,19,22) and also matches the (slightly smaller) footprint of the six TMD helices in the half-transporter MsbA (29). This area is most likely to contain the domains in closest proximity to the MHC class I binding grooves awaiting suitable peptides (40,55,56) and is also the most likely target area for the interaction of US6, the viral inhibitor of TAP expressed by human cytomegalovirus (51,57). The threedimensional structures of TAP and P-glycoprotein appear less similar from the cytoplasmic side/intracellular views ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Velarde¹,

Ford²,

Rosenberg³

et al. 2001

Journal of Biological Chemistry

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The transporter associated with antigen processing (TAP) is an ATP binding cassette transporter responsible for peptide translocation into the lumen of the endoplasmic reticulum for assembly with major histocompatibility complex class I molecules. Immunoaffinity-purified TAP particles comprising TAP1 and TAP2 polypeptides, and TAP2 particles alone were characterized after detergent solubilization and studied by electron microscopy. Projection structures of TAP1؉2 particles reveal a molecule ϳ10 nm across with a deeply staining central region, whereas TAP2 molecules are smaller in projection. A three-dimensional structure of TAP reveals it is isolated as a single heterodimeric complex, with the TAP1 and TAP2 subunits combining to create a central 3-nm-diameter pocket on the predicted endoplasmic reticulum-lumenal side. Its structural similarity to other ABC transporters demonstrates a common tertiary structure for this diverse family of membrane proteins. ATP binding cassette (ABC)1 transporters are ubiquitous and can form a significant component of an organism's genome, for example 2% in Escherichia coli (1). They are defined by the ABC domain, a nucleotide hydrolysis domain whose activity powers substrate transport (2), and are classically composed of at least four domains, two transmembrane domains (TMDs) and two cytoplasmic and soluble nucleotide binding domains (NBDs). These domains can be expressed together as a single modular polypeptide or separately.TAP is an ABC transporter expressed in the endoplasmic reticulum (ER), which supplies peptides from the cytosol for binding by MHC class I molecules (3-8). In the absence of TAP the assembly of MHC class I and, consequently, antigen presentation are both severely impaired (9 -12). TAP is expressed as two polypeptide subunits, TAP1 and TAP2, each composed of one TMD and one NBD, which together form the functional transporter. Models for the predicted structure of TAP have relied on the sequence-based prediction of multiple transmembrane-spanning regions in the TMDs (13), the location of point mutations or naturally occurring polymorphisms affecting peptide selection and transport (14 -17), or the cytosolic or ER lumenal orientation of TAPs engineered to contain reporter molecules (18,19). More recently, expression of truncated TAP polypeptides suggests interactions between both the TMDs and NBDs of . Nevertheless, no direct structural imaging of this crucial molecule to the development of cellular immune responses has yet been obtained.There is a need for structural studies of whole ABC transporters to permit insights into their overall structure and functions. Single particle image analysis has successfully been applied to molecules of comparable size to TAP (23-26). Furthermore, low resolution electron microscopic structures of the ABC transporters P-glycoprotein and MRP1 have been determined using a combination of single particle and crystallographic analysis (27,28). Recently a structure for MsbA, a prokaryotic half-ABC transporter, has been published, all...

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Section: Discussionmentioning

confidence: 99%

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Velarde¹,

Ford²,

Rosenberg³

et al. 2001

Journal of Biological Chemistry

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“…Recently it was also shown that a chaperone molecule, calnexin, mediates heavy-chain-P2-m dimerisation and binding of the dimers to TAP molecules facilitates their assembly with TAP-transported peptides. (Trowsdale et al, 1990;Kleijmeer et al, 1992;Spies et al, 1992;Ortman et al, 1994).…”

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confidence: 99%

Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer

Korkolopoulou

Kaklamanis²,

Pezzella³

et al. 1996

Br J Cancer

164

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Summary Presentation of endogenous antigenic peptides to cytotoxic T lymphocytes is mediated by the major histocompatibility complex (MHC) class I molecules. For the stable assembly of MHC class I complex it is necessary that the antigenic peptide is transported by the MHC-encoded transporters TAP-1 and TAP-2 into a pre-Golgi region. T-cell-mediated host-vs-tumour response might therefore depend on the presence of these molecules on tumour cells. The presence of MHC class I antigens and TAP-1 was studied in a series of 93 resection specimens of non-small-cell lung carcinomas (NSCLCs) by immunohistochemical methods using antibodies against the assembled class I molecule, beta2-microglobulin (02-m), heavy-chain A locus, A2 allele and TAP-1 protein. Eighty-six patients were included in the survival analysis. Total loss of class I molecule was observed in 38% of the cases and was usually accompanied by loss of ,2-m and of heavy chain A locus. Selective loss of A locus was seen in 8.3% and of A2 allele in 27% of the cases. TAP-1 loss was always combined with P2-m and/or heavy chain A locus loss. No correlation was found between the expressional status of any of the above molecules, including the selective A2 allelic loss and histological type, degree of differentiation, tumoral stage, nodal stage and survival. Our findings suggest that loss of antigen-presenting molecules (including both MHC class I alleles and TAP-1) is a frequent event in lung cancer. However, the immunophenotypic profile of MHC class I and TAP-1 seems to be unrelated in vivo to the phenotype, growth or survival of NSCLC.

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“…Fax +49 6221 563953. Brenner, 1994) and peptide transporters (Ortmann et al, 1994;Suh et al, 1994), stable association with fl2m (Kvist & Hamann, 1990), and binding of the antigenic peptide that is held in the polymorphic peptide binding groove. MHC class I molecules lacking peptide display a different conformation and are deficient with respect to surface transport and stability (Hsu et al, 1991 ;Lie et aI., 1990).…”

Section: Introductionmentioning

confidence: 99%

Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells

Hengel

Esslinger

Pool

et al. 1995

Journal of General Virology

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CD8 + cytotoxic T cell (CTL) clones with specificity for defined minor and major histocompatibility (H) antigens were used to monitor antigen presentation in human cytomegalovirus (HCMV)-infected skin fibroblasts. At the immediate early stage of virus replication antigen presentation was intact, but was abolished during the early and late phase. Lack of CTL recognition was not selective for certain antigens but was associated with decreased steady state levels of nascent MHC class I complexes and unassembled MHC class I heavy chains, whereas free fl2-microglobulin remained abundant. HCMV also affected the stability of both immature endoglycosidase H (Endo H)-sensitive and mature Endo H-resistant MHC class I molecules, suggesting that the virus interferes with antigen presentation at more than one step during maturation of the MHC class I complex. The action of interferon-y (IFN-7) and tumour necrosis factor-~ (TNF-~) lifted the block of MHC class I complex formation by stimulating synthesis, assembly and stability of MHC class I molecules. This resulted in restored antigen presentation provided that cells were exposed to the factors before HCMV infection. Because few MHC molecules suffice for CTL recognition these cytokines compensated for the negative viral effect on the antigen presentation function. Nevertheless, the viral interference with MHC class I complex formation was still active. The data imply that specific cytokines limit the immune evasion potential of HCMV from CD8 + T lymphocyte control.

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MHC class l/β2-microglobulin complexes associate with TAP transporters before peptide binding

Cited by 351 publications

References 27 publications

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Three-dimensional Structure of Transporter Associated with Antigen Processing (TAP) Obtained by Single Particle Image Analysis

Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer

Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells

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