The interaction of beta 2-microglobulin (β2m) with mouse class I major histocompatibility antigens and its ability to support peptide binding. A comparison of human and mouse β2m |
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Authors: | Lars
Pedersen Anette Stryhn Thor L Holtet Mikael Etzerodt Jens Gerwien Mogens H Nissen Hans C Thgersen Seren Buus |
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Institution: | Lars Ø. Pedersen,Anette Stryhn,Thor L. Holtet,Mikael Etzerodt,Jens Gerwien,Mogens H. Nissen,Hans C. Thøgersen,Seren Buus |
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Abstract: | The function of major histocompatibility complex (MHC) class I molecules is to sample peptides derived from intracellular proteins and to present these peptides to CD8+ cytotoxic T lymphocytes. In this paper, biochemical assays addressing MHC class I binding of both peptide and β2-microglobulin (β2m) have been used to examine the assembly of the trimolecular MHC class I/β2m/peptide complex. Recombinant human β2m and mouse β2m2 have been generated to compare the binding of the two β2m to mouse class I. It is frequently assumed that human β2m binds to mouse class I heavy chain with a much higher affinity than mouse β2m itself. We find that human β2m only binds to mouse class I heavy chain with slightly (about 3-fold) higher affinity than mouse β2m. In addition, we compared the effect of the two β2m upon peptide binding to mouse class I. The ability of human β2m to support peptide binding correlated well with its ability to saturate mouse class I heavy chains. Surprisingly, mouse β2m only facilitated peptide binding when mouse β2m was used in excess (about 20-fold) of what was needed to saturate the class I heavy chains. The inefficiency of mouse β2m to support peptide binding could not be attributed to a reduced affinity of mouse β2m/MHC class I complexes for peptides or to a reduction in the fraction of mouse β2m/MHC class I molecules participating in peptide binding. We have previously shown that only a minor fraction of class I molecules are involved in peptide binding, whereas most of class I molecules are involved in β2m binding. We propose that mouse β2m interacts with the minor peptide binding (i.e. the “empty”) fraction with a lower affinity than human β2m does, whereas mouse and human β2m interact with the major peptide-occupied fraction with almost similar affinities. This would explain why mouse β2m is less efficient than human β2m in generating the peptide binding moiety, and identifies the empty MHC class I heavy chain as the molecule that binds human β2m preferentially. |
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Keywords: | β 2-microglobulin Major histocompatibility complex class I Antigen presentation Cytotoxic T cells |
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