Mutation of the α2 domain disulfide bridge of the class I molecule HLA-A∗0201 Effect on maturation and peptide presentation

Warburton, Robert; Matsui, Masanao; Rowland‐Jones, Sarah; Gammon, Maureen C.; Katzenstein, Gil E.; Wei, Taiyin; Edidin, Michael; Zweerink, Hans J.; McMichael, Andrew J.; Frelinger, Jeffrey A.

doi:10.1016/0198-8859(94)90269-0

Cited by 49 publications

(45 citation statements)

References 34 publications

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“…In contrast, the protein levels varied greatly (50 to 100-fold difference). These results are supported by findings of Warburton et al 5 who determined a 95% decrease of cell surface HLA-A*0201 expression after performing side-directed mutagenesis of aa positions 101 and 164 in the HLA molecule. The HLA-A*3014L protein accumulates inside the cells, which indicates that HLA-A*3014L translation is not affected.…”

Section: Discussionsupporting

confidence: 86%

“…This alteration of the secondary structure is assumed to decrease the level of protein expression on the cell surface, rendering HLA-A*3014L serologically undetectable. 2,4,5 Although reportedly undetectable by standard microlymphocytotoxicity assays, we analyzed the functional integrity of HLA-A*3014L because weak expression was demonstrated when the corresponding B-lymphoblastoid cell line (B-LCL) was cultured at 30°C or exposed to cytokines at 37°C. 4,6 Here, we show for the first time that certain HLA low expression alleles present peptides, indicating that they can be functionally active.…”

Section: Introductionmentioning

confidence: 99%

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The nature of peptides presented by an HLA class I low expression allele

Hinrichs

Föll²,

Bade‐Doeding³

et al. 2010

Haematologica

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

The nature of peptides presented by an HLA class I low expression allele

Hinrichs

Föll²,

Bade‐Doeding³

et al. 2010

Haematologica

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“…MHC class I HCs are partially reduced shortly after synthesis and immediately before ER-associated degradation (ERAD), and ERp57 contributes to reduction under both circumstances (3,17). Mutation of either Cys-101 or Cys-164 in the MHC class I HC peptide-binding groove substantially inhibits peptide loading (11,18). Conversely, poor peptide loading leads to reduction of that disulfide bond and ERAD.…”

Section: Discussionmentioning

confidence: 99%

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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“…Tapasin-mediated retention serves to optimize peptide loading and thus stability, so that complexes can traffic to the cell surface and display peptides without dissociating prematurely. An important component of HC folding and assembly is the formation of correct intrachain disulfide bonds (3), as evidenced by mutations in critical Cys residues that interfere with class I expression and antigen presentation (4). For MHC class I proteins this appears to be mediated by ERp57, a thiol oxidoreductase that catalyzes disulfide bond formation and rearrangement.…”

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confidence: 99%

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

Dangoria¹,

DeLay²,

Kingsbury³

et al. 2002

Journal of Biological Chemistry

223

252

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The class I protein HLA-B27 confers susceptibility to inflammatory arthritis in humans and when overexpressed in rodents for reasons that remain unclear. We demonstrated previously that HLA-B27 heavy chains (HC) undergo endoplasmic reticulum (ER)-associated degradation. We report here that HLA-B27 HC also forms two types of aberrant disulfide-linked complexes (dimers) during the folding and assembly process that can be distinguished by conformation-sensitive antibodies W6/32 and HC10. HC10-reactive dimers form immediately after HC synthesis in the ER and constitute at least 25% of the HC pool, whereas W6/32-reactive dimers appear several hours later and represent less than 10% of the folded HC. HC10-reactive dimers accumulate in the absence of tapasin or ␤ 2 -microglobulin, whereas W6/ 32-reactive dimers are not detected. Efficient formation of W6/32-reactive dimers appears to depend on the transporter associated with antigen processing, tapasin, and ␤ 2 -microglobulin. The unpaired Cys 67 and residues at the base of the B pocket that dramatically impair HLA-B27 HC folding are critical for the formation of HC10-reactive ER dimers. Although certain other alleles also form dimers late in the assembly pathway, ER dimerization of HLA-B27 may be unique. These results demonstrate that residues comprising the HLA-B27 B pocket result in aberrant HC folding and disulfide bond formation, and thus confer unusual properties on this molecule that are unrelated to peptide selection per se, yet may be important in disease pathogenesis.

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Mutation of the α2 domain disulfide bridge of the class I molecule HLA-A∗0201 Effect on maturation and peptide presentation

Cited by 49 publications

References 34 publications

The nature of peptides presented by an HLA class I low expression allele

The nature of peptides presented by an HLA class I low expression allele

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

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

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