Quantitative and Qualitative Influences of Tapasin on the Class I Peptide Repertoire

Purcell, Anthony W.; Gorman, Jeffrey J.; García-Peydró, Marina; Paradela, Alberto; Burrows, Scott R.; Talbo, Gert; Laham, Nihay; Peh, Chen Au; Reynolds, Eric C.; Castro, José A. Łópez de; McCluskey, James

doi:10.4049/jimmunol.166.2.1016

Cited by 137 publications

(142 citation statements)

References 58 publications

(90 reference statements)

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“…The factors that determine the differences in the relative tapasin dependence of various MHC class I molecules remain elusive. Analysis of the amino acid sequence of some ligands that are loaded into B2705 in the presence and the absence of tapasin shows no clear correlation between tapasin dependence and either cellular abundance of the ligands or their binding affinities for HLA-B2705 molecule (9). Taking these findings and the relative lack of tapasin polymorphism into account (10), the MHC class I allele-dependent requirement for tapasin is likely a property of the individual MHC class I alleles.…”

mentioning

confidence: 94%

A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence

Park

Lee

Kim

et al. 2003

The Journal of Immunology

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Different HLA class I alleles display a distinctive dependence on tapasin for surface expression and Ag presentation. In this study, we show that the tapasin dependence of HLA class I alleles correlates to the nature of the amino acid residues present at the naturally polymorphic position 114. The tapasin dependence of HLA class I alleles bearing different residues at position 114 decreases in the order of acidity, with high tapasin dependence for acidic amino acids (aspartic acid and glutamic acid), moderate dependence for neutral amino acids (asparagine and glutamine), and low dependence for basic amino acids (histidine and arginine). A glutamic acid to histidine substitution at position 114 allows the otherwise tapasin-dependent HLA-B4402 alleles to load high-affinity peptides independently of tapasin and to have surface expression levels comparable to the levels seen in the presence of tapasin. The opposite substitution, histidine to glutamic acid at position 114, is sufficient to change the HLA-B2705 allele from the tapasin-independent to the tapasin-dependent phenotype. Furthermore, analysis of point mutants at position 114 reveals that tapasin plays a principal role in transforming the peptide-binding groove into a high-affinity, peptide-receptive conformation. The natural polymorphisms in HLA class I H chains that selectively affect tapasin-dependent peptide loading provide insights into the functional interaction of tapasin with MHC class I molecules.

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mentioning

confidence: 94%

A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence

Park

Lee

Kim

et al. 2003

The Journal of Immunology

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“…In addition, not only the quantity but also the quality of these peptide-HLA-I complexes is altered (11). The reason behind these differences in tapasin dependence is not known.…”

Section: Resultsmentioning

confidence: 99%

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

Røder

Geironson

Rasmussen

et al. 2011

Journal of Biological Chemistry

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A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn 1-87 , assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to established tapasin dependence hierarchies. Two large sets of HLA-A*02:01 binding peptides, one extracted from natural HLA-I ligands from the SYFPEITHI database and one consisting of medium to high affinity non-SYFPEITHI ligands, were studied in the context of HLA-A*02:01 binding and stability. We show that the SYFPEITHI peptides induced more stable HLA-A*02:01 molecules than the other ligands, although affinities were similar. Remarkably, Tpn 1-87 could functionally discriminate the selected SYFPEITHI peptides from the other peptide binders with high sensitivity and specificity. We suggest that this HLA-I-and peptide-specific function, together with the functions exerted by the more C-terminal parts of tapasin, are major features of tapasin-mediated HLA-I quality control. These findings are important for understanding the biogenesis of HLA-I molecules, the selection of presented T-cell epitopes, and the identification of immunogenic targets in both basic research and vaccine design.Mature HLA-I 3 molecules are located on the surface of all nucleated cells where they present peptides to CD8ϩ T lymphocytes. Before the peptide-HLA-I complex is transported to the cell surface, maturation and assembly with peptides occur in the ER. During late stage maturation, HLA-I molecules are integrated in the peptide-loading complex (PLC), which at least consists of TAP1/2, tapasin, calreticulin, protein disulfide isomerase, ERp57, and HLA-I (1, 2). Integration of HLA-I into the PLC is mediated by tapasin, which structurally bridges HLA-I and TAP (3, 4). Tapasin is a multi-domain protein, which has been suggested to perform multiple functions. Tapasin has been shown to enhance peptide binding to TAP, facilitate peptide loading onto HLA-I, edit the HLA-I bound peptide repertoire, and retain and recycle suboptimally loaded peptide-HLA-I complexes (5-9). Consequently, in the absence of tapasin, cell surface-expressed HLA-I molecules are less stable and present a partly different peptide repertoire than HLA-I on wild-type cells (10 -12). The effect of tapasin depends on the HLA-I allomorph where certain allomorphs, such as HLA-A*02:01, are dependent on tapasin for efficient presentation, whereas others are less influenced (10 -12).Recently, we showed that an N-terminal fragment of tapasin, Tpn 1-87 , assi...

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“…Much of the work examining tapasin function has understandably been performed using either tapasin-deficient cells (6,8,(40)(41)(42)(43)(44)(45) or mutant MHC class I molecules that no longer associate with tapasin (13,14,16,23,25). However, in tapasin-deficient cells, it is now apparent that TAPBPR is present and still capable of binding to MHC class I.…”

Section: Discussionmentioning

confidence: 99%

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

Hermann

Strittmatter

Deane

et al. 2013

The Journal of Immunology

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The loading of peptide antigens onto MHC class I molecules is a highly controlled process in which the MHC class I dedicated chaperone tapasin is a key player. We recently identified a tapasin related molecule, TAPBPR, as an additional component in the MHC class I antigen presentation pathway. Here we show that the amino acid residues important for tapasin to interact with MHC class I are highly conserved on TAPBPR. We identify specific residues in the N-terminal and C-terminal domains of TAPBPR involved in associating with MHC class I. Furthermore, we demonstrate that residues on MHC class I crucial for its association with tapasin, such as T134, are also essential for its interaction with TAPBPR. Taken together, the data indicate that TAPBPR and tapasin bind in a similar orientation to the same face of MHC class I. In the absence of tapasin, the association of MHC class I with TAPBPR is increased. However, in the absence of TAPBPR, the interaction between MHC class I and tapasin does not increase. In light of our findings, previous data determining the function of tapasin in the MHC class I antigen processing and presentation pathway must be re-evaluated.

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Quantitative and Qualitative Influences of Tapasin on the Class I Peptide Repertoire

Cited by 137 publications

References 58 publications

A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence

A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

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