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J. Biol. Chem., Vol. 282, Issue 24, 17587-17593, June 15, 2007

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

Susana G. Santos¹², Elaine C. Campbell¹, Sarah Lynch³, Vincent Wong, Antony N. Antoniou⁴, and Simon J. Powis⁵

From the Bute Medical School, University of St. Andrews, Fife KY16 9TS, Scotland, United Kingdom and Cancer Sciences Division, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom

The endoplasmic reticulum-located multimolecular peptide-loading 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.

Received for publication, March 14, 2007 , and in revised form, April 11, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by Fellowship SFRH/BPD/20964/2004 from the Portuguese Foundation for Science and Technology.

³ Supported by the University of St. Andrews Maitland-Ramsay Ph.D. studentship.

⁴ Supported by Arthritis Research Campaign UK Fellowship 15293.

⁵ To whom correspondence should be addressed. Tel.: 44-1334-463627; E-mail: sjp10{at}st-andrews.ac.uk.

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