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Dual, HLA-B27 subtype-dependent conformation of a self-peptide.

Hülsmeyer M, Fiorillo MT, Bettosini F, Sorrentino R, Saenger W, Ziegler A, Uchanska-Ziegler B - J. Exp. Med. (2004)

Bottom Line: The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules.In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709.These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

View Article: PubMed Central - PubMed

Affiliation: Institut für Kristallographie, Freie Universität Berlin, 14195 Berlin, Germany.

ABSTRACT
The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

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Final electron density of pVIPR conformations in B*2705 and B*2709. Stereo images of the final 2Fo-Fc electron density contoured at 1 σ level, displayed in light green. The two B*2705:pVIPR conformations are shown in A, the respective B*2709 complex is shown in B. The peptides are color coded as in Fig. 1 (A and B): water molecules as red and Mn2+ as green spheres.
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fig2: Final electron density of pVIPR conformations in B*2705 and B*2709. Stereo images of the final 2Fo-Fc electron density contoured at 1 σ level, displayed in light green. The two B*2705:pVIPR conformations are shown in A, the respective B*2709 complex is shown in B. The peptides are color coded as in Fig. 1 (A and B): water molecules as red and Mn2+ as green spheres.

Mentions: In addition, there is a metal binding site with an octahedral coordination sphere formed by pHis8-Nɛ, His197-Nɛ (of a symmetry-related HC), and four water molecules. The cation is probably Mn2+ as inferred from coordination distances (38). The electron density and B factors of Mn2+ (19.7 Å2 in B*2705 and 42.3 Å2 in B*2709; the B values are different due to the different resolutions) (Fig. 2 , electron densities for Mn2+) suggest that the site is fully occupied. The presence of Mn2+ is a purification artifact that originates from a lysis buffer.


Dual, HLA-B27 subtype-dependent conformation of a self-peptide.

Hülsmeyer M, Fiorillo MT, Bettosini F, Sorrentino R, Saenger W, Ziegler A, Uchanska-Ziegler B - J. Exp. Med. (2004)

Final electron density of pVIPR conformations in B*2705 and B*2709. Stereo images of the final 2Fo-Fc electron density contoured at 1 σ level, displayed in light green. The two B*2705:pVIPR conformations are shown in A, the respective B*2709 complex is shown in B. The peptides are color coded as in Fig. 1 (A and B): water molecules as red and Mn2+ as green spheres.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211767&req=5

fig2: Final electron density of pVIPR conformations in B*2705 and B*2709. Stereo images of the final 2Fo-Fc electron density contoured at 1 σ level, displayed in light green. The two B*2705:pVIPR conformations are shown in A, the respective B*2709 complex is shown in B. The peptides are color coded as in Fig. 1 (A and B): water molecules as red and Mn2+ as green spheres.
Mentions: In addition, there is a metal binding site with an octahedral coordination sphere formed by pHis8-Nɛ, His197-Nɛ (of a symmetry-related HC), and four water molecules. The cation is probably Mn2+ as inferred from coordination distances (38). The electron density and B factors of Mn2+ (19.7 Å2 in B*2705 and 42.3 Å2 in B*2709; the B values are different due to the different resolutions) (Fig. 2 , electron densities for Mn2+) suggest that the site is fully occupied. The presence of Mn2+ is a purification artifact that originates from a lysis buffer.

Bottom Line: The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules.In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709.These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

View Article: PubMed Central - PubMed

Affiliation: Institut für Kristallographie, Freie Universität Berlin, 14195 Berlin, Germany.

ABSTRACT
The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

Show MeSH
Related in: MedlinePlus