The Ig-Like Domain of Tapasin Influences Intermolecular Interactions

Turnquist, Hēth; Petersen, Jason L.; Vargas, Shanna E.; McIlhaney, Mary M.; Bedows, Elliott; Mayer, Werner E.; Grandea, Andres G.; Kaer, Luc Van; Solheim, Joyce C.

doi:10.4049/jimmunol.172.5.2976

Cited by 32 publications

(34 citation statements)

References 63 publications

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“…An additional MHC class I interaction site has been suggested on the membrane proximal domain of tapasin consisting of residues 333-342 (18)(19)(20)(21). The amino acid alignment suggests that, although R333 and S341 are conserved between the two proteins, there is considerable variation between the two molecules in this region.…”

Section: Mhc Class I Binding Sites Defined On Tapasin Are Conserved Omentioning

confidence: 99%

“…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). A second interaction point between tapasin and the MHC class I H chain involves residues 333-342 in the C-terminal Ig-like domain of tapasin (18)(19)(20)(21), which are predicted to bind residues 222-229, situated in a b strand in the a3 domain of the MHC class I heterodimer (20,(22)(23)(24)(25).…”

mentioning

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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Section: Mhc Class I Binding Sites Defined On Tapasin Are Conserved Omentioning

confidence: 99%

mentioning

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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“…Furthermore, presentation of an H2-K b -restricted epitope derived from ovalbumin was reduced in ERp57-deficient mouse B lymphocytes (6). The tapasin C95A mutation did not affect H2-K b binding of this ovalbumin-derived peptide, but mutation of Cys-95 prevented the association of H2-L d with tapasin in human cells (7,8). Thus, the relative importance of conjugate formation for PLC assembly in mouse and human systems is ambiguous.…”

mentioning

confidence: 98%

The redox activity of ERp57 is not essential for its functions in MHC class I peptide loading

Peaper

Cresswell

2008

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

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ERp57 is an oxidoreductase that, in conjunction with calnexin and calreticulin, assists disulfide bond formation in folding glycoproteins. ERp57 also forms a mixed disulfide with the MHC class I-specific chaperone tapasin, and this dimeric conjugate edits the peptide repertoire bound by MHC class I molecules. In cells unable to form the conjugate, because of tapasin mutation in human studies or ERp57 deletion in mouse studies, peptide loading is impeded. Subtle differences between the mouse and human systems have been observed. Here, we address these differences and expand the analysis to investigate the role of ERp57 redox functions in MHC class I peptide loading. We show in human cells that in the absence of conjugate formation MHC class I recruitment and/or stabilization in the MHC class I peptide-loading complex is impaired, similar to observations in mouse cells. However, we found no role for the enzymatic activities of either the a or a domain redox sites of ERp57 in peptide loading. Our data argue that the function of ERp57 in peptide loading is likely caused by other ERp57 functional domains or a combinatorial feature of the tapasin-ERp57 conjugate.antigen presentation ͉ antigen processing ͉ human ͉ protein folding ͉ quality control S table loading of peptides onto MHC class I/␤ 2 -microglobulin (␤ 2 m) dimers requires coordinated action within the peptide-loading complex (PLC), which consists of TAP1, TAP2, tapasin, ERp57, calreticulin (CRT), MHC class I heavy chain (HC), and ␤ 2 m (1). Tapasin is a critical component of the PLC, but the in vivo role of ERp57 in peptide loading and editing is not entirely resolved. ERp57 is an oxidoreductase that promotes proper disulfide bond formation in folding glycoproteins through its association(s) with calnexin (CNX) and/or CRT (2). Like protein disulfide isomerase, ERp57 is composed of four domains with the a and aЈ domains containing redox active CXXC motifs. During the biosynthetic folding of MHC class I HC, it appears to act in a manner consistent with models of glycoprotein quality control (3). However, within the PLC, Cys-57 of ERp57 forms a disulfide bond with tapasin Cys-95, and tapasin inactivates the substrate dissociation step, or ''escape pathway,'' of ERp57, making this interaction very stable (4).We examined MHC class I assembly in human B lymphoblastoid cells expressing HLA-B*4402 and a tapasin construct in which Cys-95 was mutated to Ala (C95A) to prevent conjugate formation (5). PLC formation was qualitatively normal except for the absence of ERp57, but the stability of peptide-MHC class I complexes assembled in these cells was decreased, consistent with association with a pool of lower-affinity peptides. In mouse B cells lacking ERp57, surface expression of H2-K b molecules was reduced by Ϸ50%, and turnover was faster than in ERp57-expressing cells. H2-K b recruitment into the PLC was affected, and its trafficking through the Golgi was accelerated. Furthermore, presentation of an H2-K b -restricted epitope derived from ovalbumin was reduced in E...

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“…Subsequently, it was suggested that amino acids 284 -401 mostly originating from exon 5 has an Ig-like structure (Mayer and Klein 2001). This was further elaborated on using homology modeling suggesting that 287 -401 has an Ig-like fold (Turnquist, Petersen et al 2004). After many crystallization attempts, the first protein crystal structure was reported of tapasin in a stable disulfide conjugate with ERp57 (Dong, Wearsch et al 2009).…”

Section: Tapasin Optimizes the Mhc-i Peptide Repertoire By Releasing mentioning

confidence: 99%