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An Extensive Region of an MHC Class I 2 Domain Loop Influences Interaction with the Assembly Complex¹

Yik Y. L. Yu^*, Heth R. Turnquist, Nancy B. Myers^*, Ganesaratnam K. Balendiran, Ted H. Hansen^* and Joyce C. Solheim^2,

^* Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198; and Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843

Presentation of antigenic peptides to CTLs at the cell surface first requires assembly of MHC class I with peptide and ß₂-microglobulin in the endoplasmic reticulum. This process involves an assembly complex of several proteins, including TAP, tapasin, and calreticulin, all of which associate specifically with the ß₂-microglobulin-assembled, open form of the class I heavy chain. To better comprehend at a molecular level the regulation of class I assembly, we have assessed the influence of multiple individual amino acid substitutions in the MHC class I 2 domain on interaction with TAP, tapasin, and calreticulin. In this report, we present evidence indicating that many residues surrounding position 134 in H-2L^d influence interaction with assembly complex components. Most mutations decreased association, but one (L^dK131D) strongly increased it. The L^d mutants, with the exception of L^dK131D, exhibited characteristics suggesting suboptimal intracellular peptide loading, similar to the phenotype of L^d expressed in a tapasin-deficient cell line. Notably, K131D was less peptide inducible than wild-type L^d, which is consistent with its unusually strong association with the endoplasmic reticulum assembly complex.