skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Abstract

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{sup +} 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 ({beta}Glu69). 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 {beta}Glu69. 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 withmore » 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.« less

Authors:
; ; ; ; ; ; ;  [1];  [2]
  1. (HHMI)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002407
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; Journal Volume: 107; Journal Issue: (16) ; 04, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; ARGININE; BERYLLIUM; CRYSTAL STRUCTURE; DISEASES; GENETICS; GLUTAMIC ACID; INFLAMMATION; LUNGS; MUTATIONS; PEPTIDES; RESIDUES; SOLVENTS

Citation Formats

Dai, Shaodong, Murphy, Guinevere A., Crawford, Frances, Mack, Douglas G., Falta, Michael T., Marrack, Philippa, Kappler, John W., Fontenot, Andrew P., and Colorado). Crystal structure of HLA-DP2 and implications for chronic beryllium disease. United States: N. p., 2010. Web. doi:10.1073/pnas.1001772107.
Dai, Shaodong, Murphy, Guinevere A., Crawford, Frances, Mack, Douglas G., Falta, Michael T., Marrack, Philippa, Kappler, John W., Fontenot, Andrew P., & Colorado). Crystal structure of HLA-DP2 and implications for chronic beryllium disease. United States. doi:10.1073/pnas.1001772107.
Dai, Shaodong, Murphy, Guinevere A., Crawford, Frances, Mack, Douglas G., Falta, Michael T., Marrack, Philippa, Kappler, John W., Fontenot, Andrew P., and Colorado). Tue . "Crystal structure of HLA-DP2 and implications for chronic beryllium disease". United States. doi:10.1073/pnas.1001772107.
@article{osti_1002407,
title = {Crystal structure of HLA-DP2 and implications for chronic beryllium disease},
author = {Dai, Shaodong and Murphy, Guinevere A. and Crawford, Frances and Mack, Douglas G. and Falta, Michael T. and Marrack, Philippa and Kappler, John W. and Fontenot, Andrew P. and Colorado)},
abstractNote = {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{sup +} 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 ({beta}Glu69). 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 {beta}Glu69. 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.},
doi = {10.1073/pnas.1001772107},
journal = {Proc. Natl. Acad. Sci. USA},
number = (16) ; 04, 2010,
volume = 107,
place = {United States},
year = {Tue Jun 15 00:00:00 EDT 2010},
month = {Tue Jun 15 00:00:00 EDT 2010}
}