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International Immunology, Vol. 14, No. 4, pp. 347-358, April 2002
© 2002 Japanese Society for Immunology

Mutant MHC class I molecules define interactions between components of the peptide-loading complex

Marie-Eve Paquet1 and David B. Williams1,2

Departments of 1 Immunology and 2 Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Correspondence to: D. B. Williams; E-mail: david.williams{at}utoronto.ca
Transmitting editor: H. Ploegh

Class I histocompatibility molecules, consisting of a heavy chain, ß2-microglobulin and peptide, are assembled in the endoplasmic reticulum (ER) with the assistance of several molecular chaperones and accessory proteins. Peptide binding occurs when assembling class I molecules associate with a loading complex consisting of the transporter associated with antigen processing (TAP) peptide transporter, tapasin, ERp57 and calreticulin (CRT)/calnexin. To assess the physical organization of this complex, we generated a series of mutants in the murine H-2Dd heavy chain and assessed their association with components of the complex. Seven mutations, clustered between amino acids 122 and 136 in the heavy chain {alpha}2 domain plus one mutation at position 222 in the {alpha}3 domain, resulted in loss of interaction with tapasin. Association with TAP was always lost simultaneously, supporting the view that tapasin acts as an obligatory bridge between class I molecules and TAP. Compared with previous studies on the HLA-A2 molecule, some differences in points of tapasin interaction were observed. Failure of the H-2Dd mutants to bind tapasin resulted in low cell-surface expression and altered intracellular transport. Most mutants retained a substantial degree of peptide loading, consistent with the view that although tapasin may promote peptide binding to class I, it is not required. A surprising observation was that all mutants lacking tapasin interaction retained normal association with CRT. This contrasts with previous observations on other class I molecules and, combined with differences in tapasin interaction, suggests that the organization of the ER peptide-loading complex can vary depending on the specific class I molecule examined.

Keywords: antigen presentation, calreticulin, endoplasmic reticulum, H-2Dd, histocompatibility, tapasin, transporter associated with antigen processing


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