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Presentation of a self-peptide in two distinct conformations by a disease-associated HLA-B27 subtype.

Wucherpfennig KW - J. Exp. Med. (2004)

View Article: PubMed Central - PubMed

Affiliation: Dept. of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA. Kai_Wucherpfennig@dfci.harvard.edu

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The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated... Even though susceptibility to many other human diseases has since been shown to be associated with particular alleles of MHC class I and/or class II genes, it remains one of the strongest associations between a MHC gene and a chronic inflammatory disease... An extensive search failed to identify other genes in the MHC class I region with a tighter linkage to AS, leading to the conclusion that the HLA-B gene itself is responsible... Among Caucasians, susceptibility to AS is associated with the B*2705 and B*2702 subtypes, whereas other subtypes are very rare... In contrast, the B*2706 subtype is the most prevalent among Indonesians (80%) but does not confer susceptibility to AS... Hülsmeyer et al. thus demonstrate for the first time that the same peptide can be bound by a MHC class I molecule in two grossly different conformations due to a polymorphic residue located on the floor of the binding site... Such grossly different peptide conformations are not likely to occur in MHC class II–peptide complexes, due to fundamental differences in the anchoring of peptides between MHC class I and class II proteins: conserved residues of the MHC class II binding site form hydrogen bonds along the length of the peptide backbone, and not only at the termini, and thus force the peptide into an extended conformation... This polymorphism may, therefore, influence susceptibility to AS and reactive arthritis by two mechanisms: differential binding of peptides or induction of alternative peptide conformations, as described by Hülsmeyer et al.... HLA-B27–restricted CD8 T cell clones that specifically lyse Yersinia- or Salmonella-infected target cells have been isolated from the synovial fluid of patients with reactive arthritis, but it is not known which bacterial peptide(s) are critical in the pathogenesis and whether T cell recognition of self-peptides is involved in the chronic inflammatory stage of the disease... Previous work on disease-associated MHC polymorphisms has provided a number of examples in which key MHC residues determine the peptide binding preferences and thus the repertoire of self-peptides that can be presented... For example, the DQ β57 polymorphism that is associated with susceptibility to type 1 diabetes determines the charge of the P9 pocket of the peptide binding site and thus has a drastic effect on the peptide repertoire that can be presented... The work by Hülsmeyer et al. demonstrates a novel potential mechanism by which a disease-associated MHC polymorphism can affect peptide presentation: the induction of an alternative peptide conformation that changes the peptide surface accessible for T cell receptor recognition.

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Two distinct conformations of the pVIPR peptide in the binding site of HLA-B27. Two HLA-B27 subtypes that are differentially associated with susceptibility to AS were crystallized with a self-peptide (pVIPR). The peptide bound in a conventional conformation (termed p4α, blue) to both B27 subtypes but also in a novel conformation (termed p6α, pink) to the AS-associated B*2705 subtype. In the novel conformation, the arginine at position 5 of the peptide formed a salt bridge with Asp 116 located on the floor of the peptide-binding site, the only residue that differs between the B*2705 and B*2709 subtypes. The heavy chain α1 helix and the floor of the peptide-binding site are shown (gray), whereas the α2 helix has been cut away to provide better visibility of the peptide.
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fig1: Two distinct conformations of the pVIPR peptide in the binding site of HLA-B27. Two HLA-B27 subtypes that are differentially associated with susceptibility to AS were crystallized with a self-peptide (pVIPR). The peptide bound in a conventional conformation (termed p4α, blue) to both B27 subtypes but also in a novel conformation (termed p6α, pink) to the AS-associated B*2705 subtype. In the novel conformation, the arginine at position 5 of the peptide formed a salt bridge with Asp 116 located on the floor of the peptide-binding site, the only residue that differs between the B*2705 and B*2709 subtypes. The heavy chain α1 helix and the floor of the peptide-binding site are shown (gray), whereas the α2 helix has been cut away to provide better visibility of the peptide.

Mentions: The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated. In this issue, Hülsmeyer et al. adds a new twist to the already rich literature on MHC polymorphisms and human disease (1). The authors determined the crystal structures of two HLA-B27 subtypes (B*2705 and B*2709) with the same self-peptide (pVIPR, derived from vasoactive intestinal peptide type 1 receptor). These two subtypes are remarkable in that they differ only at one heavy chain residue but are differentially associated with susceptibility to ankylosing spondylitis (AS), a chronic inflammatory joint disease. The pVIPR peptide bound in a conventional conformation to both HLA-B27 subtypes but in a second unique conformation to the AS-associated B*2705 subtype. In the conventional binding mode, an arginine at position 5 of the peptide was solvent exposed and thus available for TCR recognition. In the second conformation, this arginine instead formed a salt bridge with a buried polymorphic residue located at the floor of the binding site (Asp 116) (Fig. 1) . The drastically altered position of this central peptide residue also changed the conformation of the entire central peptide segment from positions 3 to 7 (1). A single, buried polymorphic MHC class I residue can thus affect the global conformation of a bound peptide.


Presentation of a self-peptide in two distinct conformations by a disease-associated HLA-B27 subtype.

Wucherpfennig KW - J. Exp. Med. (2004)

Two distinct conformations of the pVIPR peptide in the binding site of HLA-B27. Two HLA-B27 subtypes that are differentially associated with susceptibility to AS were crystallized with a self-peptide (pVIPR). The peptide bound in a conventional conformation (termed p4α, blue) to both B27 subtypes but also in a novel conformation (termed p6α, pink) to the AS-associated B*2705 subtype. In the novel conformation, the arginine at position 5 of the peptide formed a salt bridge with Asp 116 located on the floor of the peptide-binding site, the only residue that differs between the B*2705 and B*2709 subtypes. The heavy chain α1 helix and the floor of the peptide-binding site are shown (gray), whereas the α2 helix has been cut away to provide better visibility of the peptide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211774&req=5

fig1: Two distinct conformations of the pVIPR peptide in the binding site of HLA-B27. Two HLA-B27 subtypes that are differentially associated with susceptibility to AS were crystallized with a self-peptide (pVIPR). The peptide bound in a conventional conformation (termed p4α, blue) to both B27 subtypes but also in a novel conformation (termed p6α, pink) to the AS-associated B*2705 subtype. In the novel conformation, the arginine at position 5 of the peptide formed a salt bridge with Asp 116 located on the floor of the peptide-binding site, the only residue that differs between the B*2705 and B*2709 subtypes. The heavy chain α1 helix and the floor of the peptide-binding site are shown (gray), whereas the α2 helix has been cut away to provide better visibility of the peptide.
Mentions: The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated. In this issue, Hülsmeyer et al. adds a new twist to the already rich literature on MHC polymorphisms and human disease (1). The authors determined the crystal structures of two HLA-B27 subtypes (B*2705 and B*2709) with the same self-peptide (pVIPR, derived from vasoactive intestinal peptide type 1 receptor). These two subtypes are remarkable in that they differ only at one heavy chain residue but are differentially associated with susceptibility to ankylosing spondylitis (AS), a chronic inflammatory joint disease. The pVIPR peptide bound in a conventional conformation to both HLA-B27 subtypes but in a second unique conformation to the AS-associated B*2705 subtype. In the conventional binding mode, an arginine at position 5 of the peptide was solvent exposed and thus available for TCR recognition. In the second conformation, this arginine instead formed a salt bridge with a buried polymorphic residue located at the floor of the binding site (Asp 116) (Fig. 1) . The drastically altered position of this central peptide residue also changed the conformation of the entire central peptide segment from positions 3 to 7 (1). A single, buried polymorphic MHC class I residue can thus affect the global conformation of a bound peptide.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA. Kai_Wucherpfennig@dfci.harvard.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated... Even though susceptibility to many other human diseases has since been shown to be associated with particular alleles of MHC class I and/or class II genes, it remains one of the strongest associations between a MHC gene and a chronic inflammatory disease... An extensive search failed to identify other genes in the MHC class I region with a tighter linkage to AS, leading to the conclusion that the HLA-B gene itself is responsible... Among Caucasians, susceptibility to AS is associated with the B*2705 and B*2702 subtypes, whereas other subtypes are very rare... In contrast, the B*2706 subtype is the most prevalent among Indonesians (80%) but does not confer susceptibility to AS... Hülsmeyer et al. thus demonstrate for the first time that the same peptide can be bound by a MHC class I molecule in two grossly different conformations due to a polymorphic residue located on the floor of the binding site... Such grossly different peptide conformations are not likely to occur in MHC class II–peptide complexes, due to fundamental differences in the anchoring of peptides between MHC class I and class II proteins: conserved residues of the MHC class II binding site form hydrogen bonds along the length of the peptide backbone, and not only at the termini, and thus force the peptide into an extended conformation... This polymorphism may, therefore, influence susceptibility to AS and reactive arthritis by two mechanisms: differential binding of peptides or induction of alternative peptide conformations, as described by Hülsmeyer et al.... HLA-B27–restricted CD8 T cell clones that specifically lyse Yersinia- or Salmonella-infected target cells have been isolated from the synovial fluid of patients with reactive arthritis, but it is not known which bacterial peptide(s) are critical in the pathogenesis and whether T cell recognition of self-peptides is involved in the chronic inflammatory stage of the disease... Previous work on disease-associated MHC polymorphisms has provided a number of examples in which key MHC residues determine the peptide binding preferences and thus the repertoire of self-peptides that can be presented... For example, the DQ β57 polymorphism that is associated with susceptibility to type 1 diabetes determines the charge of the P9 pocket of the peptide binding site and thus has a drastic effect on the peptide repertoire that can be presented... The work by Hülsmeyer et al. demonstrates a novel potential mechanism by which a disease-associated MHC polymorphism can affect peptide presentation: the induction of an alternative peptide conformation that changes the peptide surface accessible for T cell receptor recognition.

Show MeSH
Related in: MedlinePlus