A Charged Amino Acid Residue in the Transmembrane/Cytoplasmic Region of Tapasin Influences MHC Class I Assembly and Maturation

Petersen, Jason L.; Hickman, Heather D.; McIlhaney, Mary M.; Vargas, Shanna E.; Purcell, Anthony W.; Hildebrand, William H.; Solheim, Joyce C.

doi:10.4049/jimmunol.174.2.962

Cited by 42 publications

(44 citation statements)

References 49 publications

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“…Interestingly, we found that it is only the integral membrane components of the PLC, TAP, and Tpn that are dependent upon MHCI expression. Consistently, the TM domain of Tpn is known to be important for both its interaction with MHCI (45,53,54) and TAP (55). Although TM interactions are known to be important for the assembly of multimeric complexes such as the TCR-CD3 complex (56), our findings suggest TM interactions are also critical for monitoring the disassembly of MHC-PLC complexes and targeting them for ERAD.…”

Section: Discussionsupporting

confidence: 57%

Newly Discovered Viral E3 Ligase pK3 Induces Endoplasmic Reticulum-associated Degradation of Class I Major Histocompatibility Proteins and Their Membrane-bound Chaperones

Herr

Wang

Loh

et al. 2012

Journal of Biological Chemistry

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Background: Viral E3 ubiquitin ligases use distinct mechanisms to degrade proteins required for antigen presentation. Results: Novel viral ligase, pK3, binds to MHCI proteins and induces degradation of MHCI and associated ER chaperones. Conclusion: pK3 uses a novel mechanism to recognize substrates and block antigen presentation. Significance: Demonstrates the importance of transmembrane interactions in E3:substrate interaction and ER quality control.

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Section: Discussionsupporting

confidence: 57%

Newly Discovered Viral E3 Ligase pK3 Induces Endoplasmic Reticulum-associated Degradation of Class I Major Histocompatibility Proteins and Their Membrane-bound Chaperones

Herr

Wang

Loh

et al. 2012

Journal of Biological Chemistry

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“…Third, TAPBPR is not an integral component of the PLC. In keeping with this, TAPBPR lacks a charged residue in its transmembrane domain, a property of tapasin that is proposed to facilitate its interaction with TAP (15,30). Fourth, TAPBPR expression is not restricted to the ER.…”

Section: Discussionmentioning

confidence: 95%

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

Boyle

Hermann

Boname

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

153

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Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled with β2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. β2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR: MHC class I complex trafficks through the Golgi apparatus, demonstrating a function of TAPBPR beyond the endoplasmic reticulum/ cis-Golgi. The identification of TAPBPR as an additional component of the MHC class I antigen-presentation pathway demonstrates that mechanisms controlling MHC class I expression remain incompletely understood.

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“…Because of the multi-functionality of tapasin, it seems plausible that different domains or regions of the protein contribute with different functions. Indeed, it has been shown that an ER retention/ recycling motif and TAP interaction interface are located at the C-terminal part of tapasin (21,22). The cysteine in position 95 in the ER luminal part of tapasin forms a disulfide conjugate with ERp57, and this conjugation has been proposed to be required for tapasin peptide editing (23).…”

Section: Discussionmentioning

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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A Charged Amino Acid Residue in the Transmembrane/Cytoplasmic Region of Tapasin Influences MHC Class I Assembly and Maturation

Cited by 42 publications

References 49 publications

Newly Discovered Viral E3 Ligase pK3 Induces Endoplasmic Reticulum-associated Degradation of Class I Major Histocompatibility Proteins and Their Membrane-bound Chaperones

Newly Discovered Viral E3 Ligase pK3 Induces Endoplasmic Reticulum-associated Degradation of Class I Major Histocompatibility Proteins and Their Membrane-bound Chaperones

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

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

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