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J. Exp. Med., Volume 187, Number 6, March 16, 1998 865-874

Physical and Functional Association of the Major Histocompatibility Complex Class I Heavy Chain alpha 3 Domain with the Transporter Associated with Antigen Processing

By Kimary Kulig,* Dipankar Nandi,Dagger Igor Bacík,§ John J. Monaco, and Stanislav Vukmanovic'*

From the * Michael Heidelberger Division of Immunology, the Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York 10016; the Dagger  Department of Biochemistry, Indian Institute of Science, Bangalore, India 560012; § Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892; and the  Department of Molecular Genetics, Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, Ohio 45267

CD8+ T lymphocytes recognize antigens as short, MHC class I-associated peptides derived by processing of cytoplasmic proteins. The transporter associated with antigen processing translocates peptides from the cytosol into the ER lumen, where they bind to the nascent class I molecules. To date, the precise location of the class I-TAP interaction site remains unclear. We provide evidence that this site is contained within the heavy chain alpha 3 domain. Substitution of a 15 amino acid portion of the H-2Db alpha 3 domain (aa 219-233) with the analogous MHC class II (H-2IAd) beta 2 domain region (aa 133-147) results in loss of surface expression which can be partially restored upon incubation at 26°C in the presence of excess peptide and beta 2-microglobulin. Mutant H-2Db (Db219-233) associates poorly with the TAP complex, and cannot present endogenously-derived antigenic peptides requiring TAP-dependent translocation to the ER. However, this presentation defect can be overcome through use of an ER targeting sequence which bypasses TAP-dependent peptide translocation. Thus, the alpha 3 domain serves as an important site of interaction (directly or indirectly) with the TAP complex and is necessary for TAP-dependent peptide loading and class I surface expression.


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