Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.
The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.
Siebold
Christian
C
Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Hansen
Bjarke E
BE
Wyer
Jessica R
JR
Harlos
Karl
K
Esnouf
Robert E
RE
Svejgaard
Arne
A
Bell
John I
JI
Strominger
Jack L
JL
Jones
E Yvonne
EY
Fugger
Lars
L
D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006801:Humans; D008562:Membrane Glycoproteins; D008958:Models, Molecular; D009290:Narcolepsy / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D008562:Membrane Glycoproteins