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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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pVIPR conformations, atomic displacement ellipsoids, and B factors. (A) Superimposition of the canonical pVIPR conformations (p4α) found in B*2705 (blue) and B*2709 (gold). (B) The noncanonical pVIPR conformation (p6α, pink) observed only in B*2705. The peptides are viewed from the side of the α2 helix together with a molecular surface covering the floor and back of the binding groove. The subtype-specific residue 116 is indicated also (Asp116, yellow; His116, turquoise); the bidentate salt bridge to Asp116 is drawn with green dotted lines in B. The binding pockets A–F are shown in bold letters. Atomic displacement ellipsoids for pVIPR-p4α and -p6α in C and D are colored according to the equivalent isotropic temperature factors B (Å2) (see color bar). (E, left) Schematic description of side chain orientation when looking from the NH2 to the COOH terminus of pVIPR. Bottom of peptide binding groove indicated by “β-sheet” and side for T cell recognition by “TCR”. (E, right) The orientation of the peptide side chains in the p4α and p6α conformations as in E (left). The respective binding pockets (A–F) are indicated as well. It is clear from this representation and Fig. 1 (A and B) that the two pVIPR conformations show major differences only from pLys3 to pTrp7.
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fig1: pVIPR conformations, atomic displacement ellipsoids, and B factors. (A) Superimposition of the canonical pVIPR conformations (p4α) found in B*2705 (blue) and B*2709 (gold). (B) The noncanonical pVIPR conformation (p6α, pink) observed only in B*2705. The peptides are viewed from the side of the α2 helix together with a molecular surface covering the floor and back of the binding groove. The subtype-specific residue 116 is indicated also (Asp116, yellow; His116, turquoise); the bidentate salt bridge to Asp116 is drawn with green dotted lines in B. The binding pockets A–F are shown in bold letters. Atomic displacement ellipsoids for pVIPR-p4α and -p6α in C and D are colored according to the equivalent isotropic temperature factors B (Å2) (see color bar). (E, left) Schematic description of side chain orientation when looking from the NH2 to the COOH terminus of pVIPR. Bottom of peptide binding groove indicated by “β-sheet” and side for T cell recognition by “TCR”. (E, right) The orientation of the peptide side chains in the p4α and p6α conformations as in E (left). The respective binding pockets (A–F) are indicated as well. It is clear from this representation and Fig. 1 (A and B) that the two pVIPR conformations show major differences only from pLys3 to pTrp7.

Mentions: HLA-B*2705:pVIPR and B*2709:pVIPR crystallized isomorphously (same space group and comparable unit cell constants), showing the typical MHC class I immunoglobulin-like folds (1) and refined to values of Rcryst = 12.8% and Rfree = 17.8% at 1.47 Å and Rcryst = 18.8% and Rfree = 24.4% at 2.20 Å resolution, respectively (Materials and Methods and Table I). In both structures, pVIPR is bound in the common canonical conformation (Fig. 1 A) found in other HLA-B27 molecules, exploiting all six pockets of the peptide binding groove for interaction with the HC (19, 36, 37). However, B*2705:pVIPR features an additional, grossly different noncanonical peptide conformation (Fig. 1 B). Both conformations found in B*2705 are present in a 1:1 ratio as shown by occupancy refinement. Despite this peculiarity in B*2705, the structures of HC and β2m of the two subtypes are practically indistinguishable (Cα root mean square [rms] deviation 0.2 Å), including almost all side chain atoms. The atoms contributing to the binding groove occupy the same positions in B*2705 as in B*2709, and extreme atomic displacement factors (thermal anisotropy), which could mask multiple conformations were also not detected for B*2705. It has to be emphasized that, due to the isomorphous crystal structures, the intermolecular crystal contacts in both B*2705:pVIPR conformations are comparable, demonstrating that the two different binding modes of pVIPR found only in B*2705 are an intrinsic feature due to the presence of Asp116 and not a crystallographic artifact.


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)

pVIPR conformations, atomic displacement ellipsoids, and B factors. (A) Superimposition of the canonical pVIPR conformations (p4α) found in B*2705 (blue) and B*2709 (gold). (B) The noncanonical pVIPR conformation (p6α, pink) observed only in B*2705. The peptides are viewed from the side of the α2 helix together with a molecular surface covering the floor and back of the binding groove. The subtype-specific residue 116 is indicated also (Asp116, yellow; His116, turquoise); the bidentate salt bridge to Asp116 is drawn with green dotted lines in B. The binding pockets A–F are shown in bold letters. Atomic displacement ellipsoids for pVIPR-p4α and -p6α in C and D are colored according to the equivalent isotropic temperature factors B (Å2) (see color bar). (E, left) Schematic description of side chain orientation when looking from the NH2 to the COOH terminus of pVIPR. Bottom of peptide binding groove indicated by “β-sheet” and side for T cell recognition by “TCR”. (E, right) The orientation of the peptide side chains in the p4α and p6α conformations as in E (left). The respective binding pockets (A–F) are indicated as well. It is clear from this representation and Fig. 1 (A and B) that the two pVIPR conformations show major differences only from pLys3 to pTrp7.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211767&req=5

fig1: pVIPR conformations, atomic displacement ellipsoids, and B factors. (A) Superimposition of the canonical pVIPR conformations (p4α) found in B*2705 (blue) and B*2709 (gold). (B) The noncanonical pVIPR conformation (p6α, pink) observed only in B*2705. The peptides are viewed from the side of the α2 helix together with a molecular surface covering the floor and back of the binding groove. The subtype-specific residue 116 is indicated also (Asp116, yellow; His116, turquoise); the bidentate salt bridge to Asp116 is drawn with green dotted lines in B. The binding pockets A–F are shown in bold letters. Atomic displacement ellipsoids for pVIPR-p4α and -p6α in C and D are colored according to the equivalent isotropic temperature factors B (Å2) (see color bar). (E, left) Schematic description of side chain orientation when looking from the NH2 to the COOH terminus of pVIPR. Bottom of peptide binding groove indicated by “β-sheet” and side for T cell recognition by “TCR”. (E, right) The orientation of the peptide side chains in the p4α and p6α conformations as in E (left). The respective binding pockets (A–F) are indicated as well. It is clear from this representation and Fig. 1 (A and B) that the two pVIPR conformations show major differences only from pLys3 to pTrp7.
Mentions: HLA-B*2705:pVIPR and B*2709:pVIPR crystallized isomorphously (same space group and comparable unit cell constants), showing the typical MHC class I immunoglobulin-like folds (1) and refined to values of Rcryst = 12.8% and Rfree = 17.8% at 1.47 Å and Rcryst = 18.8% and Rfree = 24.4% at 2.20 Å resolution, respectively (Materials and Methods and Table I). In both structures, pVIPR is bound in the common canonical conformation (Fig. 1 A) found in other HLA-B27 molecules, exploiting all six pockets of the peptide binding groove for interaction with the HC (19, 36, 37). However, B*2705:pVIPR features an additional, grossly different noncanonical peptide conformation (Fig. 1 B). Both conformations found in B*2705 are present in a 1:1 ratio as shown by occupancy refinement. Despite this peculiarity in B*2705, the structures of HC and β2m of the two subtypes are practically indistinguishable (Cα root mean square [rms] deviation 0.2 Å), including almost all side chain atoms. The atoms contributing to the binding groove occupy the same positions in B*2705 as in B*2709, and extreme atomic displacement factors (thermal anisotropy), which could mask multiple conformations were also not detected for B*2705. It has to be emphasized that, due to the isomorphous crystal structures, the intermolecular crystal contacts in both B*2705:pVIPR conformations are comparable, demonstrating that the two different binding modes of pVIPR found only in B*2705 are an intrinsic feature due to the presence of Asp116 and not a crystallographic artifact.

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