Insights into MHC Class I Peptide Loading from the Structure of the Tapasin-ERp57 Thiol Oxidoreductase Heterodimer

Dong, Gang; Wearsch, Pamela A.; Peaper, David R.; Cresswell, Peter; Reinisch, Karin M

doi:10.1016/j.immuni.2008.10.018

Cited by 260 publications

(369 citation statements)

References 54 publications

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“…The N-terminal domain of tapasin is essential for association and peptide loading of MHC class I (11). By comparing the sequences of tapasin from different species and screening mutant tapasin molecules, Dong et al (12) identified a region of the N-terminal domain of tapasin that interacts with MHC class I. This cluster of residues on tapasin includes E185, R187, Q189, H190, L191, K193, L250, and Q261 defined by the panel of tapasin TN mutants (TN3, TN4, TN5, TN6, TN7).…”

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confidence: 99%

“…This cluster of residues on tapasin includes E185, R187, Q189, H190, L191, K193, L250, and Q261 defined by the panel of tapasin TN mutants (TN3, TN4, TN5, TN6, TN7). This region of tapasin is predicted to bind a loop consisting of residues 128-136 below the a2-1 helix of the MHC class I heterodimer (12)(13)(14)(15). Residues in the predicted contact site in MHC class I (e.g., T134) are essential for incorporation of MHC class I into the peptide loading complex and efficient peptide loading (13)(14)(15)(16)(17).…”

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confidence: 99%

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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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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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“…Exclusion of the exon 3 encoded region (tpn residues 50-137) interrupts the structure of the shorter N-terminal stalk found in the L-shaped form of tpn [36]. Cys-95, forming a covalent bond with the oxidoreductase ERp57 [29] is therefore lost, whereas the C-terminal structure should remain unchanged.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the tpn transmembrane/cytosolic region and the tpn C-terminal Ig-like domain, a structure which should be retained in TPSN Ex3, contribute to the efficiency of tpn to interact with MHC-I [39]. Several contact sites for MHC-I on tpn have recently been defined [36], of these only Glu-72 is missing in TPSN Ex3, which could be the reason for the loss of stable TPSN Ex3-MHC-I interaction. Also, Roder et al [22] demonstrated that the first 87 residues of tpn are sufficient to stabilize MHC-I and peptide loading.…”

Section: Discussionmentioning

confidence: 99%

“…ac.il/) have been described to control alternative splicing in several cases [32][33][34]. Specifically, it has been shown that these proteins are able to enhance the usage of upstream splice donor sites [35] as observed for the G-runs in intron 3 of tpn.Exclusion of the exon 3 encoded region (tpn residues 50-137) interrupts the structure of the shorter N-terminal stalk found in the L-shaped form of tpn [36]. Cys-95, forming a covalent bond with the oxidoreductase ERp57 [29] is therefore lost, whereas the C-terminal structure should remain unchanged.…”

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A natural tapasin isoform lacking exon 3 modifies peptide loading complex function

et al. 2013

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To assure efficient MHC class I (MHC-I) peptide loading, the peptide loading complex (PLC) recruits the peptide-receptive form of MHC-I, and in this process, tapasin (tpn) connects MHC-I with the peptide transporter TAP and forms a stable disulfide bond with ERp57. Here, we describe an alternatively spliced tpn transcript lacking exon 3, observed in cells infected with human cytomegalovirus. Recognition of exon 3 was regulated via G-runs, suggesting that members of the hnRNP (heterogeneous nuclear ribonucleoprotein)-family regulate expression of the Exon3 variant of tpn. Exon 3 includes Cys-95, which is responsible for the disulfide bond formation with ERp57 and, consequently, interaction of the Exon3 variant with ERp57 was strongly impaired. Although the Exon3 variant specifically stabilized TAP expression but not MHC-I in tpn-deficient cells, in tpn-proficient cells, the Exon3 tpn reduced cell surface expression of the tpn-dependent HLA-B*44:02 allele; the stability of the tpn-independent HLA-B*44:05 was not affected. Most importantly, detailed analysis of the PLC revealed a simultaneous binding of the Exon3 variant and tpn to TAP, suggesting modification of PLC functions. Indeed, an altered MHC-I ligandome was observed in HeLa cells overexpressing the Exon3 variant, highlighting the potential of the alternatively spliced tpn variant to impact CD8 + T-cell responses.Keywords: MHC class I peptide loading r PLC r TAP r Tapasin Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Anne Halenius e-mail: anne.halenius@uniklink-freiburg.de * These authors contributed equally to this work. Eur. J. Immunol. 2013Immunol. . 43: 1459Immunol. -1469 Introduction Presentation of endogenous peptides by MHC class I (MHC-I) to CD8 + T cells is critical to controlling viral infections and tumor growth. Peptides originating from cytosolic proteasomal degradation are translocated into the ER lumen by the heterodimeric peptide transporter TAP1/2 (transporter associated with Ag processing). Optimally TAP transports peptides with a length of 8-16 amino acids [1,2] and these can be further trimmed in the ER to fit the peptide binding groove of MHC class I (MHC-I) molecules [3], yielding a stable peptide-MHC-I complex that is transported through the secretory pathway for cell surface expression. Proper peptide loading of MHC-I is controlled by several chaperones that form the peptide loading complex (PLC) in the ER [4]. In the PLC the MHC-I heterodimer associates with tapasin (tpn), calreticulin, ERp57, and indirectly with TAP; tpn and TAP interact via their transmembrane segments (TMSs), thereby stabilizing the structure and function of TAP [5][6][7][8][9]. It has been shown that both TAP1 and TAP2 subunits possess binding sites for tpn at their N-terminal TMSs [10][11][12]. The exact stoichiometry of the PLC has been a matter of debate [13,14]; however, recent findings demonstrate a TAP-tpn ratio of 1:2 [15,16] as proposed previously also by Rufer et al...

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Structural Basis of Disulfide Bond Formation in the Bacterial Periplasm and Mammalian ER

Kojima

Okumura

Inaba

2013

Encyclopedia of Life Sciences

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Cellular quality control systems rely on the maintenance of protein and redox homoeostasis, in which the formation, reduction and isomerisation of protein disulfide bonds play important roles. The biological kingdoms have evolved catalytic systems that greatly promote oxidative protein folding. Remarkable progress in structural biology in this field has provided molecular views on how protein disulfide bonds are generated de novo and transferred to downstream folding substrates. Very recently, a novel concept has emerged, proposing that multiple oxidative pathways work redundantly, distinctly and in a complementary manner in the endoplasmic reticulum of mammalian cells to efficiently produce large quantities, and a wide variety, of secretory proteins. Thus, the oxidative protein folding network is even more complicated in higher eukaryotes than previously thought. Key Concepts: Almost all organisms, from bacteria to humans, possess catalytic systems that promote protein‐disulfide bond formation. Disulfide bond formation networks have diversified dramatically, as evidenced by the appearance of a large number of disulfide oxidoreductases in higher eukaryotes. High‐resolution structures have been solved for an increasing number of disulfide oxidoreductases, thereby revealing the structural and mechanistic basis of cellular disulfide bond formation systems. Disulfide bonds play an important role in folding, assembly and stabilisation of various proteins. Disulfide bond formation networks are closely related to the protein and redox homeostasis in the cell.

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Insights into MHC Class I Peptide Loading from the Structure of the Tapasin-ERp57 Thiol Oxidoreductase Heterodimer

Cited by 260 publications

References 54 publications

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

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

A natural tapasin isoform lacking exon 3 modifies peptide loading complex function

Structural Basis of Disulfide Bond Formation in the Bacterial Periplasm and Mammalian ER

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