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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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Related in: MedlinePlus

Molecular surfaces and contacts of pVIPR in the p4α and p6α conformations. (A and B) Molecular surfaces show the central part of the B*2705 peptide binding groove in gray and the pVIPR peptide in the p4α and p6α conformations (color coded as in Fig. 1 [A and B]). The binding groove has been rendered semi-transparent, allowing also the inspection of buried side chains exhibiting conformational differences. In A, the view is TCR-like, straight onto the peptide, whereas in B (rotated by 90° about a horizontal axis), the view is through the α2 helix. The center section of the peptide shows clear shape differences between the p4α and p6α conformations. (C) pVIPR hydrogen bonding in p4α and p6α, color coded as in Fig 1 (A and B). Only side chains with different binding modes (residues p3–p7) are shown. The binding groove's secondary structure is represented as gray spirals (α helices) and arrows (β strands) together with selected interacting residues (carbon atoms, gray; oxygens, red; and nitrogens, blue). Hydrogen bonds are depicted as black broken lines, the pArg5–Asp116 bidentate salt bridge is depicted as green dotted lines, and water molecules are depicted as dark blue spheres. (D) Electrostatic surfaces of both pVIPR conformations. Red indicates negative, blue indicates positive surface charge, and gray areas are uncharged. The view is looking straight onto the binding groove as in A. The border of the peptides is highlighted in white.
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fig3: Molecular surfaces and contacts of pVIPR in the p4α and p6α conformations. (A and B) Molecular surfaces show the central part of the B*2705 peptide binding groove in gray and the pVIPR peptide in the p4α and p6α conformations (color coded as in Fig. 1 [A and B]). The binding groove has been rendered semi-transparent, allowing also the inspection of buried side chains exhibiting conformational differences. In A, the view is TCR-like, straight onto the peptide, whereas in B (rotated by 90° about a horizontal axis), the view is through the α2 helix. The center section of the peptide shows clear shape differences between the p4α and p6α conformations. (C) pVIPR hydrogen bonding in p4α and p6α, color coded as in Fig 1 (A and B). Only side chains with different binding modes (residues p3–p7) are shown. The binding groove's secondary structure is represented as gray spirals (α helices) and arrows (β strands) together with selected interacting residues (carbon atoms, gray; oxygens, red; and nitrogens, blue). Hydrogen bonds are depicted as black broken lines, the pArg5–Asp116 bidentate salt bridge is depicted as green dotted lines, and water molecules are depicted as dark blue spheres. (D) Electrostatic surfaces of both pVIPR conformations. Red indicates negative, blue indicates positive surface charge, and gray areas are uncharged. The view is looking straight onto the binding groove as in A. The border of the peptides is highlighted in white.

Mentions: At the peptide NH2- and COOH-termini, pArg1, pArg2, pHis8, and pLeu9 occupy identical positions in pVIPR-p4α and -p6α (Fig. 1, A, B, and E and Fig. 2 A). The interactions of pArg1 and pArg2 with A and B pocket residues correspond to those observed for the B*2709:s10R complex (PDB code 1JGD; reference 37); the side chain of pArg1 is sandwiched between the side chains of HC Arg62 (α1-helix) and Trp167 (α2-helix). In addition, the side chains of Arg62 and Glu163 (α2-helix) are linked by a water-mediated salt bridge (Fig. 3, A and B , bridge) that covers the deeply embedded pArg2. At the COOH terminus, pHis8 is solvent exposed as well (Figs. 2 and 3), and pLeu9 is accommodated in the F pocket. The carboxy group of pLeu9 forms the common polar interactions with Tyr84-Oη, Thr143-Oγ, and Lys146-Nζ (1), and the aliphatic pLeu9 side chain forms hydrophobic interactions with the side chains of Leu81, Leu95, Tyr123, and Trp147 (19). Because the side chain of pLeu9 is too short to engage in any direct contacts with Asp116 (B*2705) or His116 (B*2709), there are no significant differences in the F pockets between both subtypes.


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)

Molecular surfaces and contacts of pVIPR in the p4α and p6α conformations. (A and B) Molecular surfaces show the central part of the B*2705 peptide binding groove in gray and the pVIPR peptide in the p4α and p6α conformations (color coded as in Fig. 1 [A and B]). The binding groove has been rendered semi-transparent, allowing also the inspection of buried side chains exhibiting conformational differences. In A, the view is TCR-like, straight onto the peptide, whereas in B (rotated by 90° about a horizontal axis), the view is through the α2 helix. The center section of the peptide shows clear shape differences between the p4α and p6α conformations. (C) pVIPR hydrogen bonding in p4α and p6α, color coded as in Fig 1 (A and B). Only side chains with different binding modes (residues p3–p7) are shown. The binding groove's secondary structure is represented as gray spirals (α helices) and arrows (β strands) together with selected interacting residues (carbon atoms, gray; oxygens, red; and nitrogens, blue). Hydrogen bonds are depicted as black broken lines, the pArg5–Asp116 bidentate salt bridge is depicted as green dotted lines, and water molecules are depicted as dark blue spheres. (D) Electrostatic surfaces of both pVIPR conformations. Red indicates negative, blue indicates positive surface charge, and gray areas are uncharged. The view is looking straight onto the binding groove as in A. The border of the peptides is highlighted in white.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211767&req=5

fig3: Molecular surfaces and contacts of pVIPR in the p4α and p6α conformations. (A and B) Molecular surfaces show the central part of the B*2705 peptide binding groove in gray and the pVIPR peptide in the p4α and p6α conformations (color coded as in Fig. 1 [A and B]). The binding groove has been rendered semi-transparent, allowing also the inspection of buried side chains exhibiting conformational differences. In A, the view is TCR-like, straight onto the peptide, whereas in B (rotated by 90° about a horizontal axis), the view is through the α2 helix. The center section of the peptide shows clear shape differences between the p4α and p6α conformations. (C) pVIPR hydrogen bonding in p4α and p6α, color coded as in Fig 1 (A and B). Only side chains with different binding modes (residues p3–p7) are shown. The binding groove's secondary structure is represented as gray spirals (α helices) and arrows (β strands) together with selected interacting residues (carbon atoms, gray; oxygens, red; and nitrogens, blue). Hydrogen bonds are depicted as black broken lines, the pArg5–Asp116 bidentate salt bridge is depicted as green dotted lines, and water molecules are depicted as dark blue spheres. (D) Electrostatic surfaces of both pVIPR conformations. Red indicates negative, blue indicates positive surface charge, and gray areas are uncharged. The view is looking straight onto the binding groove as in A. The border of the peptides is highlighted in white.
Mentions: At the peptide NH2- and COOH-termini, pArg1, pArg2, pHis8, and pLeu9 occupy identical positions in pVIPR-p4α and -p6α (Fig. 1, A, B, and E and Fig. 2 A). The interactions of pArg1 and pArg2 with A and B pocket residues correspond to those observed for the B*2709:s10R complex (PDB code 1JGD; reference 37); the side chain of pArg1 is sandwiched between the side chains of HC Arg62 (α1-helix) and Trp167 (α2-helix). In addition, the side chains of Arg62 and Glu163 (α2-helix) are linked by a water-mediated salt bridge (Fig. 3, A and B , bridge) that covers the deeply embedded pArg2. At the COOH terminus, pHis8 is solvent exposed as well (Figs. 2 and 3), and pLeu9 is accommodated in the F pocket. The carboxy group of pLeu9 forms the common polar interactions with Tyr84-Oη, Thr143-Oγ, and Lys146-Nζ (1), and the aliphatic pLeu9 side chain forms hydrophobic interactions with the side chains of Leu81, Leu95, Tyr123, and Trp147 (19). Because the side chain of pLeu9 is too short to engage in any direct contacts with Asp116 (B*2705) or His116 (B*2709), there are no significant differences in the F pockets between both subtypes.

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