Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au.
Murine experimental allergic encephalomyelitis (EAE) is a useful model for the demyelinating, autoimmune disease multiple sclerosis. In the EAE system, the immunodominant N-terminal epitope of myelin basic protein (MBP) is an unusually short, weakly binding peptide antigen which elicits highly biased TCR chain usage. In the 2.2 A crystal structure of I-A(u)/MBP1-11 complex, only MBP residues 1-7 are bound toward one end of the peptide binding cleft. The fourth residue of MBP1-11 is located in an incompatible p6 pocket of I-A(u), thus explaining the short half-life of I-A(u) complexed with Ac1-11. MBP peptides extended at the C terminus of Ac1-11 result in dramatic affinity increases, likely attributed to register shifting to a higher affinity cryptic epitope, which could potentially mask the presentation of the immunodominant MBP1-11 peptide during thymic education.
He
Xiao-lin
XL
Department of Microbiology and Immunology, Stanford University School of Medicine, CA 94305, USA.
Radu
Caius
C
Sidney
John
J
Sette
Alessandro
A
Ward
E Sally
ES
Garcia
K Christopher
KC
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001120:Arginine / Q000737:chemistry; D015551:Autoimmunity; D001665:Binding Sites; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006825:Hybridomas; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D016415:Sequence Alignment
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D046911:Macromolecular Substances; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C405722:myelin basic protein 1-11; D001120:Arginine