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

Journal Article · Tue Jun 15 04:00:00 EDT 2010 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.1001772107· OSTI ID:1002407

Dai, Shaodong; Murphy, Guinevere A; Crawford, Frances; Mack, Douglas G; Falta, Michael T; Marrack, Philippa; Kappler, John W; Fontenot, Andrew P ^[1]

---

1. HHMI

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002407
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (16) ; 04, 2010 Vol. 107; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ARGININE
BERYLLIUM
CRYSTAL STRUCTURE
DISEASES
GENETICS
GLUTAMIC ACID
INFLAMMATION
LUNGS
MUTATIONS
PEPTIDES
RESIDUES
SOLVENTS