ER60/ERp57 forms disulfide‐bonded intermediates with MHC class I heavy chain

Lindquist, Jonathan A.; Hämmerling, Günter J.; Trowsdale, John

doi:10.1096/fj.00-0720fje

Cited by 65 publications

(47 citation statements)

References 73 publications

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“…Indeed, protein folding intermediates have been shown to form transient mixed disulfides with members of the proteindisulfide isomerase family, including protein-disulfide isomerase and ERp57 (57). This has also been demonstrated for MHC class I HC in two studies, one using an in vitro translation system with microsomes (58), and in the other using a highly sensitive immunoblotting technique with 125 I-labeled anti-ER60 (ERp57) (59). In the latter studies, HC⅐ERp57 complexes were estimated to comprise Ͻ1% of the total HC pool, consistent with the notion that they are transient folding intermediates.…”

Section: Discussionmentioning

confidence: 89%

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

225

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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Section: Discussionmentioning

confidence: 89%

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

225

252

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“…Although interactions between ERp57 and MHC class I molecules have been reported (15,27), it has not been possible to determine at what stage of the assembly process these interactions occur. Indeed, rather than readily finding MHC class I interactions, it was somewhat against expectations to find that the complete pool of ERp57 within the PLC was disulfide-bonded to tapasin (19).…”

Section: Discussionmentioning

confidence: 99%

Major Histocompatibility Complex Class I-ERp57-Tapasin Interactions within the Peptide-loading Complex

Santos

Campbell

Lynch

et al. 2007

Journal of Biological Chemistry

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The endoplasmic reticulum-located multimolecular peptideloading complex functions to load optimal peptides onto major histocompatibility complex (MHC) class I molecules for presentation to CD8 ؉ T lymphocytes. Two oxidoreductases, ERp57 and protein-disulfide isomerase, are known to be components of the peptide-loading complex. Within the peptide-loading complex ERp57 is normally found disulfide-linked to tapasin, through one of its two thioredoxin-like redox motifs. We describe here a novel trimeric complex that disulfide links together MHC class I heavy chain, ERp57 and tapasin, and that is found in association with the transporter associated with antigen processing peptide transporter. The trimeric complex normally represents a small subset of the total ERp57-tapasin pool but can be significantly increased by altering intracellular oxidizing conditions. Direct mutation of a conserved structural cysteine residue implicates an interaction between ERp57 and the MHC class I peptide-binding groove. Taken together, our studies demonstrate for the first time that ERp57 directly interacts with MHC class I molecules within the peptide-loading complex and suggest that ERp57 and protein-disulfide isomerase act in concert to regulate the redox status of MHC class I during antigen presentation.To bind a high affinity, optimized pool of peptides, MHC 6 class I molecules undergo a series of chaperone-mediated interactions within the endoplasmic reticulum (ER) (1, 2). For most MHC class I molecules, this process occurs in the multicomponent MHC class I peptide-loading complex (PLC), which in addition to ␤ 2 -microglobulin (␤2m)-associated MHC class I molecules includes the chaperone calreticulin, the oxidoreductases ERp57 and protein-disulfide isomerase (PDI), the class I-specific accessory molecule tapasin, and the peptide transporter TAP (3-5). A series of experimental reports have indicated that the PLC acts cooperatively, and that the absence of any of the components results in the disruption of MHC class I assembly, and a reduction in the efficiency of antigen presentation to T cells (6 -9).Both ERp57 and PDI are integral components of the PLC (10 -12). These oxidoreductases are related to thioredoxin (TR) and share two functional CXXC motifs (denoted TR1 and TR2) (13-15). Possession of this motif permits family members to catalyze reduction, oxidation, and isomerization of disulfide bonds within substrate polypeptides (16). ERp57 normally appears to be in a GSH-dependent reduced state within the ER (17, 18), and is thus likely to be involved in reduction or isomerization reactions. However, a striking feature of ERp57 is that, in the presence of tapasin, it preferentially forms an interaction through its TR1 motif with an unpaired cysteine in tapasin at position 95 (19). The normal escape pathway that exists to release ERp57 from substrate polypeptides is inhibited by this interaction (20), leading to the whole cellular pool of tapasin being disulfide-linked to ERp57, and a large pool of cellular ERp57 being likewise oc...

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“…2B) (Russell et al, 2004;Silvennoinen et al, 2004). The frequent finding that association of ERp57 with glycoprotein substrates can be prevented by treatment with CST or expression in Cnx-deficient cells has led to the commonly held view that ERp57 is always recruited to folding glycoproteins through its interactions with Cnx or Crt (Lindquist et al, 2001;Molinari and Helenius, 1999;Oliver et al, 1997). This view is supported by the in vitro finding that the oxidative folding of monoglucosylated RNAse B by ERp57 is dramatically enhanced by the presence of Cnx or Crt (Zapun et al, 1998).…”

Section: Erp57 -A Thiol Oxidoreductase With Diverse Modes Of Substratmentioning

confidence: 99%

Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum

Williams

2006

Journal of Cell Science

428

359

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The structure of the ER-luminal portion of Cnx, solved by Xray crystallography (Schrag et al., 2001), reveals two domains: a globular ␤-sandwich domain that resembles legume lectins; and an extended 140 Å arm domain consisting of two ␤-strands folded in a hairpin configuration ( Fig. 2A). Each ␤-strand is composed of four tandemly repeated, proline-rich repeats, which is why the extended arm is frequently referred to as the P domain. For Crt, only the arm domain structure has been solved by NMR methods. It is similar to that of Cnx but shorter,

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ER60/ERp57 forms disulfide‐bonded intermediates with MHC class I heavy chain

Cited by 65 publications

References 73 publications

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

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

Major Histocompatibility Complex Class I-ERp57-Tapasin Interactions within the Peptide-loading Complex

Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum

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