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Intracellular Cysteine Residues in the Tail of MHC Class I Proteins Are Crucial for Extracellular Recognition by Leukocyte Ig-Like Receptor 1¹

Raizy Gruda^*, Hagit Achdout^*, Noam Stern-Ginossar^*, Roi Gazit^*, Gili Betser-Cohen^*, Irit Manaster^*, Gil Katz^*, Tsufit Gonen-Gross^*, Boaz Tirosh and Ofer Mandelboim^2,*

^* Lautenberg Center for General and Tumor Immunology, Hebrew University, Hadassah Medical School, Jerusalem, Israel; and Department of Pharmacology, School of Pharmacy, Hebrew University, Jerusalem, Israel

The activity of NK cells is regulated by activating receptors that recognize mainly stress-induced ligands and by inhibitory receptors that recognize mostly MHC class I proteins on target cells. Comparing the cytoplasmic tail sequences of various MHC class I proteins revealed the presence of unique cysteine residues in some of the MHC class I molecules which are absent in others. To study the role of these unique cysteines, we performed site specific mutagenesis, generating MHC class I molecules lacking these cysteines, and demonstrated that their expression on the cell surface was impaired. Surprisingly, we demonstrated that these cysteines are crucial for the surface binding of the leukocyte Ig-like receptor 1 inhibitory receptor to the MHC class I proteins, but not for the binding of the KIR2DL1 inhibitory receptor. In addition, we demonstrated that the cysteine residues in the cytoplasmic tail of MHC class I proteins are crucial for their egress from the endoplasmic reticulum and for their palmitoylation, thus probably affecting their expression on the cell surface. Finally, we show that the cysteine residues are important for proper extracellular conformation. Thus, although the interaction between leukocyte Ig-like receptor 1 and MHC class I proteins is formed between two extracellular surfaces, the intracellular components of MHC class I proteins play a crucial role in this recognition.

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 This work was supported by the Israel Science Foundation (to O.M.), Binational Science Foundation (to O.M.), Israel Ministry of Health, Israel Cancer Research Foundation, Association of International Cancer Research, Ministry of Health, and European Commission (LSHC-CT-2002-518178 and MRTN-CT-2005 to O.M.).

² Address correspondence and reprint requests to Dr. Ofer Mandelboim, Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Israel Biomedical Research Center, Jerusalem Ein Karem, Israel. E-mail address: oferm{at}ekmd.huji.ac.il or oferman{at}md2.huji.ac.il

³ Abbreviations used in this paper: ER, endoplasmic reticulum; KIR, killer Ig-like receptor; LIR, leukocyte Ig-like receptor; EndoH, endoglycosidase H; CT, cytoplasmic tail; WT, wild type; MFI, mean fluorescence intensity.

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