J. Exp. Med., Volume 187, Number 9, May 4, 1998 1505-1516

Evidence That the Autoimmune Antigen Myelin Basic Protein (MBP) Ac1-9 Binds Towards One End of the Major Histocompatibility Complex (MHC) Cleft

By Christopher Lee,^* Michael N. Liang,^* Keri M. Tate, Joshua D. Rabinowitz,^* Craig Beeson,^* Patricia P. Jones, and Harden M. McConnell^*

From the ^* Department of Chemistry and  Department of Biological Sciences, Stanford University, Stanford, California 94305-5080

The NH₂-terminal peptide of myelin basic protein (MBP) bound to the class II major histocompatibility complex (MHC) protein I-A^u is an immunodominant epitope in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. However, the MBP-I-A^u complex is very unstable. To investigate this, we performed site-directed mutagenesis of the I-A^u MHC protein and the MBP peptide. Biochemical, T cell activation, and molecular modeling studies of mutant complexes demonstrate that the MBP peptide's key residue for MHC binding, lysine 4, is buried in the P6 pocket of I-A^u, which is predominantly hydrophobic. This implies that the MBP-I-A^u complex differs from more stable complexes in two respects: (a) the peptide leaves the NH₂-terminal region of the MHC peptide-binding cleft unoccupied; (b) the peptide is not anchored by typical favorable interactions between peptide side chains and MHC pockets. To test these hypotheses, a modified MBP peptide was designed based on molecular modeling, with the aim of producing strong I-A^u binding. Extension of the NH₂ terminus of MBP with six amino acids from the ova peptide, and replacement of the lysine side chain in the P6 pocket with an aromatic anchor, results in >1,000-fold increased binding stability. These results provide an explanation for the unusual peptide-MHC-binding kinetics of MBP, and should facilitate an understanding of why mice are not tolerant to this self-peptide- MHC complex.

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