The N-terminal region of tapasin is required to stabilize the MHC class I loading complex

Bangia, Naveen; Lehner, Paul J.; Hughes, Eric; Surman, Michael; Cresswell, Peter

doi:10.1002/(sici)1521-4141(199906)29:06<1858::aid-immu1858>3.0.co;2-c

Cited by 143 publications

(151 citation statements)

References 37 publications

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“…In the presence of tapasin, the majority of K b hc remained sensitive to endo H digestion up to 120 min, reflecting retention of these molecules in the ER of these APC over this period. This rate of class I maturation is similar to that observed for HLA B8 expressed in .220 cells cotransfected with human tapasin (42). Conversely, in the absence of tapasin, the majority of K b hc had acquired resistance to endo H by 60 min.…”

Section: High-level Surface Expression Of H-2k B Class I Molecules Onsupporting

confidence: 81%

“…TAP interaction is mediated through the C terminus of tapasin (9) and has recently been shown to enhance peptide binding to the cytosolic aspect of TAP molecules (8). This implies that tapasin may enhance TAPmediated translocation of antigenic oligopeptides; however, bridging of class I molecules to the TAP does not necessarily lead to enhanced peptide loading (42,53). Therefore, it has been postulated that the class I-tapasin interaction is more critical for class I assembly than is the tapasin-mediated bridging to the TAP (9).…”

Section: Discussionmentioning

confidence: 99%

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Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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The murine class I H-2Kb molecule achieves high level surface expression in tapasin-deficient 721.220 human cells. Compared with their behavior in wild-type cells, Kb molecules expressed on 721.220 cells are more receptive to exogenous peptide, undergo more rapid surface decay, and fail to form macromolecular peptide loading complexes. As a result, they are rapidly transported to the cell surface, reflecting a failure of endoplasmic reticulum retention mechanisms in the absence of loading complex formation. Despite the failure of Kb molecules to colocalize to the TAP and their rapid egress to the cell surface, Kb is still capable of presenting TAP-dependent peptides in the absence of tapasin. Furthermore, pool sequencing of peptides eluted from these molecules revealed strict conservation of their canonical H-2Kb-binding motif. There was a reduction in the total recovery of peptides associated with Kb molecules purified from the surface of tapasin-deficient cells. Comparison of the peptides bound to Kb in the presence and absence of tapasin revealed considerable overlap in peptide repertoire. These results indicate that in the absence of an interaction with tapasin, Kb molecules fail to assemble with calreticulin and TAP, yet they are still capable of acquiring a diverse array of peptides. However, a significant proportion of these peptides appear to be suboptimal, resulting in reduced cell surface stability of Kb complexes. Taken together, the findings indicate that tapasin plays an essential role in the formation of the class I loading complex, which retains class I heterodimers in the endoplasmic reticulum until optimal ligand selection is completed.

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Section: High-level Surface Expression Of H-2k B Class I Molecules Onsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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“…Tapasin, a type I membrane glycoprotein consisting of two immunoglobulin folds and of an N-terminal domain, bears several important functions in the peptide-loading complex. First, it stabilizes TAP as TAP expression is drastically decreased in tapasin-deficient cells [5,25,51,75]. Second, by MHC class I binding and recruitment of ERp57 [19,71], tapasin coordinates and facilitates peptide loading of MHC class I molecules [50,62,83,92,102].…”

Section: Tap Is the Key Component Of The Mhc Class I Peptide-loading mentioning

confidence: 99%

Intracellular peptide transporters in human – compartmentalization of the “peptidome”

Herget

Tampé

2006

Pflugers Arch - Eur J Physiol

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In the human genome, the five adenosine triphosphate (ATP)-binding cassette (ABC) half transporters ABCB2 (TAP1), ABCB3 (TAP2), ABCB9 (TAP-like), and in part, also ABCB8 and ABCB10 are closely related with regard to their structural and functional properties. Although targeted to different cellular compartments such as the endoplasmic reticulum (ER), lysosomes, and mitochondria, they are involved in intracellular peptide trafficking across membranes. The transporter associated with antigen processing (TAP1 and TAP2) constitute a key machinery in the major histocompatibility complex (MHC) class I-mediated cellular immune defense against infected or malignantly transformed cells. TAP translocates the cellular "peptidome" derived primarily from cytosolic proteasomal degradation into the ER lumen for presentation by MHC class I molecules. The homodimeric ABCB9 (TAP-like) complex located in lysosomal compartments shares structural and functional similarities to TAP; however, its biological role seems to be different from the MHC I antigen processing. ABCB8 and ABCB10 are targeted to the inner mitochondrial membrane. MDL1, the yeast homologue of ABCB10, is involved in the export of peptides derived from proteolysis of inner-membrane proteins into the intermembrane space. As such peptides are presented as minor histocompatibility antigens on the surface of mammalian cells, a physiological role of ABCB10 in the antigen processing can be accounted.

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“…11 It mediates an interaction between TAP and newly synthesised MHC class I molecules through two functional sites; one binds to and stabilises the TAP heterodimer and the other associates to the peptide-receptive MHC class I complex. 12 The TAP protein is more stable when associated with tapasin, and peptide binding to TAP and translocation of peptides into the ER are increased when tapasin is present. Tapasin also plays an active role in the association of peptide-receptive MHC class I complexes with the other ER cofactors and is absolutely required for the association of MHC class I complexes with ERp57 and calreticulin within the PLC.…”

Section: Introductionmentioning

confidence: 99%

“…21 The TAP-binding site has been localised to exons 6-8. 12 Accordingly, an engineered construct of tapasin comprising its lumenal domains is secreted and has been shown to restore the antigenpresenting function of HLA-B8 in a tapasin-negative cell line in the absence of HLA-B8 association with TAP. 22 The N-terminal 50 amino acids of tapasin (encoded within exon 2) are essential for its interaction with class I MHC, CRT and Erp57, while a mutant mouse tapasin lacking amino acids 334-342 (encoded within exon 5) fails to bind to a mouse class I allele, but surprisingly, facilitates its assembly and expression.…”

Section: Introductionmentioning

confidence: 99%

Generation of a functional, soluble tapasin protein from an alternatively spliced mRNA

et al. 2003

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The loading of newly synthesised MHC class I molecules (MHCI) with peptides requires the involvement of several endoplasmic reticulum (ER)-resident cofactors including calnexin, calreticulin, transporter associated with antigen processing, ERp57 and tapasin. In the absence of tapasin, MHC I complexes are loaded with suboptimal peptides and their recognition by cytotoxic T cells raised to high-affinity, immunodominant peptide epitopes is impaired. Here, we describe the cloning and functional assessment of an alternative spliced form of tapasin. From the EST database, we obtained a partially spliced tapasin cDNA that retained introns 4-6. When transfected into the tapasin-deficient cell line 0.220, the cDNA produced an alternatively spliced tapasin transcript that contained intron 5 (74 bp). This introduced a new stop codon that terminated translation immediately before the putative transmembrane domain and led to a tapasin molecule containing the lumenal domain plus 8 extra novel amino acids at its C-terminus. This molecule promoted peptide loading of HLA-B5 in 0.220 cell line, and restored normal HLA-B5 surface expression. However, the peptides loaded onto HLA-B5 were suboptimal compared to those loaded onto HLA-B5 in the presence of wild-type tapasin.

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The N-terminal region of tapasin is required to stabilize the MHC class I loading complex

Cited by 143 publications

References 37 publications

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Intracellular peptide transporters in human – compartmentalization of the “peptidome”

Generation of a functional, soluble tapasin protein from an alternatively spliced mRNA

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