Limits...
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.

Show MeSH

Related in: MedlinePlus

Conformation-dependent peptide contacts with F-pocket residues. The F-pocket architecture and intermolecular interactions in B*2705:pVIPR-p4α (left) and -p6α (right), with relevant part of the peptide shown (same color code as in Fig. 1 [A and B]). Fully occupied water molecules are shown in dark blue and partially occupied ones (related to a specific peptide conformation) are in turquoise. The space occupied by pArg5-p6α is filled by water molecules in the p4α binding mode. The view is looking along the binding groove with the peptide COOH terminus in front.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211767&req=5

fig4: Conformation-dependent peptide contacts with F-pocket residues. The F-pocket architecture and intermolecular interactions in B*2705:pVIPR-p4α (left) and -p6α (right), with relevant part of the peptide shown (same color code as in Fig. 1 [A and B]). Fully occupied water molecules are shown in dark blue and partially occupied ones (related to a specific peptide conformation) are in turquoise. The space occupied by pArg5-p6α is filled by water molecules in the p4α binding mode. The view is looking along the binding groove with the peptide COOH terminus in front.

Mentions: In contrast to the NH2- and COOH-terminal residues, the central sections of pVIPR-p4α and -p6α, pLys3 to pTrp7, which are principally accessible for recognition by a TCR, differ drastically with maximal disparity at pArg5, 3.7 Å for Cα, and 16.5 Å for Nη2 (Table II and Figs. 1, A, B, and E and Fig. 2 A and Figs. 3 and 4) . In pVIPR-p4α, side chains of pTrp4 and pArg5 are exposed to solvent, but in pVIPR-p6α, pArg5 is locked within the binding groove, its guanidinium group forming a bidentate salt bridge with the B*2705 subtype-specific Asp116 at the interface of the C, E, and F pockets (Figs. 1 B and 2 C and Figs. 3 and 4). In pVIPR-p6α, residues pTrp4 and pArg6 flanking pArg5 are maximally exposed to solvent and stacked (Fig. 1 B and Fig. 2). As a consequence of the structural differences around pArg5, the solvent-accessible surface areas of pVIPR-p4α and pVIPR-p6α have different size (160 Å2 for pVIPR-p4α and 124 Å2 for pVIPR-p6α), shape (Fig. 3, A and B), and charge distribution (Fig. 3 D) so that several prerequisites for differential recognition by a TCR are provided.


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)

Conformation-dependent peptide contacts with F-pocket residues. The F-pocket architecture and intermolecular interactions in B*2705:pVIPR-p4α (left) and -p6α (right), with relevant part of the peptide shown (same color code as in Fig. 1 [A and B]). Fully occupied water molecules are shown in dark blue and partially occupied ones (related to a specific peptide conformation) are in turquoise. The space occupied by pArg5-p6α is filled by water molecules in the p4α binding mode. The view is looking along the binding groove with the peptide COOH terminus in front.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Conformation-dependent peptide contacts with F-pocket residues. The F-pocket architecture and intermolecular interactions in B*2705:pVIPR-p4α (left) and -p6α (right), with relevant part of the peptide shown (same color code as in Fig. 1 [A and B]). Fully occupied water molecules are shown in dark blue and partially occupied ones (related to a specific peptide conformation) are in turquoise. The space occupied by pArg5-p6α is filled by water molecules in the p4α binding mode. The view is looking along the binding groove with the peptide COOH terminus in front.
Mentions: In contrast to the NH2- and COOH-terminal residues, the central sections of pVIPR-p4α and -p6α, pLys3 to pTrp7, which are principally accessible for recognition by a TCR, differ drastically with maximal disparity at pArg5, 3.7 Å for Cα, and 16.5 Å for Nη2 (Table II and Figs. 1, A, B, and E and Fig. 2 A and Figs. 3 and 4) . In pVIPR-p4α, side chains of pTrp4 and pArg5 are exposed to solvent, but in pVIPR-p6α, pArg5 is locked within the binding groove, its guanidinium group forming a bidentate salt bridge with the B*2705 subtype-specific Asp116 at the interface of the C, E, and F pockets (Figs. 1 B and 2 C and Figs. 3 and 4). In pVIPR-p6α, residues pTrp4 and pArg6 flanking pArg5 are maximally exposed to solvent and stacked (Fig. 1 B and Fig. 2). As a consequence of the structural differences around pArg5, the solvent-accessible surface areas of pVIPR-p4α and pVIPR-p6α have different size (160 Å2 for pVIPR-p4α and 124 Å2 for pVIPR-p6α), shape (Fig. 3, A and B), and charge distribution (Fig. 3 D) so that several prerequisites for differential recognition by a TCR are provided.

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