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J. Biol. Chem., Vol. 279, Issue 52, 54210-54215, December 24, 2004

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Calreticulin Promotes Folding of Functional Human Leukocyte Antigen Class I Molecules in Vitro^*

Slobodan Culina, Grégoire Lauvau, Brigitte Gubler, and Peter M. van Endert¶

From the Institut National de la Santé et de la Recherche Médicale Unité 580, Université René Descartes Paris V, 75015 Paris, France

The assembly of MHC class I molecules with ₂-microglobulin and peptides is assisted by the housekeeping chaperones calnexin, calreticulin, and Erp57 and the dedicated accessory protein, tapasin. Tapasin and calreticulin are essential for efficient MHC class I assembly, but their precise action during class I assembly remains to be elucidated. Previous in vitro studies have demonstrated that the lectin calreticulin interacts with monoglucosylated MHC class I heavy chains, whatever their state of assembly with light chains and peptide, and inhibits their aggregation above physiological temperature. We used a soluble single chain HLA-A2/₂-microglobulin molecule, A2SC, to study the effect of calreticulin on the peptide binding capacity of HLA class I molecules. Calreticulin inhibited the formation of A2SC aggregates both when co-expressed in insect cells and during incubations at elevated temperature. Calreticulin dramatically enhanced acquisition of peptide binding capacity when added to denatured A2SC molecules during refolding at 4 °C. However, it had no effect on the rapid loss of A2SC peptide binding capacity at physiological temperature. We conclude that calreticulin promotes the folding of HLA class I molecules to a state in which, at low temperature, they spontaneously acquire peptide binding capacity. However, it does not induce or maintain a peptide-receptive state of the class I-binding site, which is likely to be promoted by one or several other components of the class I loading complexes. By being amenable to complementation with additional proteins, the described system should be useful for identification of these components.

Received for publication, September 21, 2004 , and in revised form, October 19, 2004.

^* This work was supported in part by a grant (to P. M. v. E.) from the Association pour la Recherche sur le Cancer, by a fellowship (to G. L.) from the Ligue Contre Le Cancer, and by fellowships (to B. G. and G. L.) from the Fondation pour la Recherche Médicale. 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.

Both authors contributed equally to this work.

Present address: INSERM E344, Institut de Pharmacologie Moléculaire et Cellulaire Sophia-Antipolis, 660 route des Lucioles, 06560 Valbonne, France.

^¶ To whom correspondence should be addressed: INSERM U 580, 161 rue de Sèvres, 75015 Paris, France. Tel.: 33144492563; Fax: 33144495382; E-mail: vanendert{at}necker.fr.

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