Crystal structure of HLA-DP2 and implications for chronic beryllium disease.
Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD4(+) T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the beta-chain (betaGlu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR alpha-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 beta-chain alpha-helix and containing three glutamic acids from the beta-chain, including betaGlu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.
Dai
Shaodong
S
Howard Hughes Medical Institute and National Jewish Health, Denver, CO 80206, USA. dais@njhealth.org
Murphy
Guinevere A
GA
Crawford
Frances
F
Mack
Douglas G
DG
Falta
Michael T
MT
Marrack
Philippa
P
Kappler
John W
JW
Fontenot
Andrew P
AP
D000483:Alleles; D000818:Animals; D001607:Berylliosis / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D018360:Crystallography, X-Ray / Q000379:methods; D018698:Glutamic Acid / Q000737:chemistry; D006682:HLA-DP Antigens / Q000737:chemistry*; D059868:HLA-DP beta-Chains; D006801:Humans; D008171:Lung Diseases / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary
D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D010455:Peptides; D018698:Glutamic Acid