Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 416K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lee, C. Articles by McConnell, H. M. Search for Related Content PubMed PubMed Citation Articles by Lee, C. Articles by McConnell, H. M. Social Bookmarking                            What's this?

Articles

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.

Christopher Lee's present address is Department of Chemistry & Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095. Michael N. Liang's present address is Department of Chemistry, Harvard University, Cambridge, MA 02138. Keri M. Tate's present address is Anergen Inc., Redwood City, CA 94603. Craig Beeson's present address is Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195-1700.

Abbreviations used: CLIP, class II–associated invariant chain peptide; D-ala, D-alanine; DM, dodecyl maltoside; EAE, experimental autoimmune encephalomyelitis; HPSEC, high-performance size exclusion chromatography; MBP, myelin basic protein.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Stephens, L. A., Gray, D., Anderton, S. M. (2005). CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc. Natl. Acad. Sci. USA 102: 17418-17423 [Abstract] [Full Text]  
• Ryan, K. R., McCue, D., Anderton, S. M. (2005). Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation. J. Leukoc. Biol. 78: 43-50 [Abstract] [Full Text]  
• Huang, J. C., Han, M., Minguela, A., Pastor, S., Qadri, A., Ward, E. S. (2003). T Cell Recognition of Distinct Peptide:I-Au Conformers in Murine Experimental Autoimmune Encephalomyelitis. J. Immunol. 171: 2467-2477 [Abstract] [Full Text]  
• Maverakis, E., Beech, J., Stevens, D. B., Ametani, A., Brossay, L., van den Elzen, P., Mendoza, R., Thai, Q., Macias, L. H., Ethell, D., Campagnoni, C. W., Campagnoni, A. T., Sette, A., Sercarz, E. E. (2003). Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC. Proc. Natl. Acad. Sci. USA 100: 5342-5347 [Abstract] [Full Text]  
• Koonce, C. H., Wutz, G., Robertson, E. J., Vogt, A. B., Kropshofer, H., Bikoff, E. K. (2003). DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements. J. Immunol. 170: 3751-3761 [Abstract] [Full Text]  
• Garcia, K. C., Radu, C. G., Ho, J., Ober, R. J., Ward, E. S. (2001). Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 98: 6818-6823 [Abstract] [Full Text]  
• Anderton, S. M., Radu, C. G., Lowrey, P. A., Ward, E. S., Wraith, D. C. (2001). Negative Selection during the Peripheral Immune Response to Antigen. JEM 193: 1-12 [Abstract] [Full Text]  
• Radu, C. G., Anderton, S. M., Firan, M., Wraith, D. C., Ward, E. S. (2000). Detection of autoreactive T cells in H-2u mice using peptide-MHC multimers. Int Immunol 12: 1553-1560 [Abstract] [Full Text]  
• Herman, A. E., Tisch, R. M., Patel, S. D., Parry, S. L., Olson, J., Noble, J. A., Cope, A. P., Cox, B., Congia, M., McDevitt2, H. O. (1999). Determination of Glutamic Acid Decarboxylase 65 Peptides Presented by the Type I Diabetes-Associated HLA-DQ8 Class II Molecule Identifies an Immunogenic Peptide Motif. J. Immunol. 163: 6275-6282 [Abstract] [Full Text]  
• Grogan, J. L., Kramer, A., Nogai, A., Dong, L., Ohde, M., Schneider-Mergener, J., Kamradt, T. (1999). Cross-Reactivity of Myelin Basic Protein-Specific T Cells with Multiple Microbial Peptides: Experimental Autoimmune Encephalomyelitis Induction in TCR Transgenic Mice. J. Immunol. 163: 3764-3770 [Abstract] [Full Text]  
• Kenty, G., Bikoff, E. K. (1999). BALB/c Invariant Chain Mutant Mice Display Relatively Efficient Maturation of CD4+ T Cells in the Periphery and Secondary Proliferative Responses Elicited upon Peptide Challenge. J. Immunol. 163: 232-241 [Abstract] [Full Text]  
• Pearson, C. I., Gautam, A. M., Rulifson, I. C., Liblau, R. S., McDevitt, H. O. (1999). A small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Ac1-11. Proc. Natl. Acad. Sci. USA 96: 197-202 [Abstract] [Full Text]  
• Anderton, S. M., Manickasingham, S. P., Burkhart, C., Luckcuck, T. A., Holland, S. J., Lamont, A. G., Wraith, D. C. (1998). Fine Specificity of the Myelin-Reactive T Cell Repertoire: Implications for TCR Antagonism in Autoimmunity. J. Immunol. 161: 3357-3364 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS