Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants. Implications for susceptibility to spondylarthropathies.

Boisgerault, Florence; Tieng, Vannary; Stolzenberg, Marie-Claude; Dulphy, Nicolas; Khalil, I.; Tamouza, Ryad; Charron, Dominique; Toubert, Antoine

doi:10.1172/jci119102

Cited by 58 publications

(35 citation statements)

References 41 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, the increased frequencies of basic P3 and PC-2 residues, and Y3, in B*27:04 and B*27:06, are presumably because of the V152E change in both subtypes and to the H114D change in B*27:06. The high frequency of N-terminal basic residues in B*27:03, which extends previous observations (22,23), is thought to be a compensatory effect of interactions between basic P1 side chains and E163, for the altered hydrogen bonding of the peptidic N terminus in the A pocket of this subtype (54).…”

Section: ϫ4supporting

confidence: 84%

“…All these subtypes have the same structure in the A and B pockets of their peptide binding site, which accommodate the two N-terminal residues of their peptide ligands, but they differ in one or more positions in the F pocket, which binds the C-terminal peptide residue, as well as in other positions of the peptide binding site. In contrast, B*27:03, a subtype prevalent only in populations of Sub-Saharan African ancestry, differs from the B*27:05 prototype by a single Y59H change in the A pocket (20,21), a difference that also sets it apart from all other subtypes (supplemental Table S1) and affects the binding preferences for N-terminal peptide residues (22)(23)(24). The nature of B*27:03 as a putative susceptibility factor for AS is unclear (19).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Peptide Handling by HLA-B27 Subtypes Influences Their Biological Behavior, Association with Ankylosing Spondylitis and Susceptibility to Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

García-Medel

Sanz-Bravo

Alvarez-Navarro

et al. 2014

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

HLA-B27 is strongly associated with ankylosing spondylitis (AS). We analyzed the relationship between structure, peptide specificity, folding, and stability of the seven major HLA-B27 subtypes to determine the role of their constitutive peptidomes in the pathogenicity of this molecule. Identification of large numbers of ligands allowed us to define the differences among subtype-bound peptidomes and to elucidate the peptide features associated with AS and molecular stability. The peptides identified only in AS-associated or high thermostability subtypes with identical A and B pockets were longer and had bulkier and more diverse C-terminal residues than those found only among non-AS-associated/lower-thermostability subtypes. Peptides sequenced from all AS-associated subtypes and not from non-AS-associated ones, thus strictly correlating with disease, were very rare. Residue 116 was critical in determining peptide binding, thermodynamic properties, and folding, thus emerging as a key feature that unified HLA-B27 biology. HLA-B27 ligands were better suited to TAP transport than their N-terminal precursors, and ASassociated subtype ligands were better than those from non-AS-associated subtypes, suggesting a particular capacity of AS-associated subtypes to bind epitopes directly produced in the cytosol. Peptides identified only from ASassociated/high-thermostability subtypes showed a higher frequency of ERAP1-resistant N-terminal residues than ligands found only in non-AS-associated/low-thermostability subtypes, reflecting a more pronounced effect of ERAP1 on the former group. Our results reveal the basis for the relationship between peptide specificity and other features of HLA-B27, provide a unified view of HLA-B27 biology and pathogenicity, and suggest a larger influence of ERAP1 polymorphism on AS-associated than non-AS-associated subtypes. Molecular & Cellular

show abstract

Section: ϫ4supporting

confidence: 84%

mentioning

confidence: 99%

Peptide Handling by HLA-B27 Subtypes Influences Their Biological Behavior, Association with Ankylosing Spondylitis and Susceptibility to Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

García-Medel

Sanz-Bravo

Alvarez-Navarro

et al. 2014

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…van der Waals interactions with Trp-167 are also important with bulky aromatic P1 residues, such as the Tyr-1 found in the only sequenced C67S-specific ligand. Significantly, an even stronger bias toward basic P1 residues than that observed in C67S was reported for B*2703 (48,49). This allotype has an unusual mutation affecting an otherwise conserved residue in the A pocket, which weakens anchoring of the peptidic N terminus (50,51).…”

Section: Discussionmentioning

confidence: 83%

The Cys-67 Residue of HLA-B27 Influences Cell Surface Stability, Peptide Specificity, and T-cell Antigen Presentation

Álvarez

Martı́

Vázquez

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cys-67 of HLA-B27 is located in the B pocket, which determines peptide-binding specificity. We analyzed effects of the Cys-67 3 Ser mutation on cell surface expression, peptide specificity, and T-cell recognition of HLA-B*2705. Surface expression was assessed with antibodies recognizing either native or unfolded HLA proteins. Whereas native B*2705 molecules predominated over unfolded ones, this ratio was reversed in the mutant, suggesting lower stability. Comparison of B*2705-and Cys-67 3 Ser-bound peptides revealed that the mutant failed to bind ϳ15% of the B*2705 ligands, while binding as many novel ones. Two peptides with Gln-2 found in both B*2705 and Cys-67 3 Ser are the first demonstration of natural B*2705 ligands lacking Arg-2. Other effects of the mutation on peptide specificity were: 1) average molecular mass of natural ligands higher than for B*2705, 2) bias against small residues at peptide position (P) 1, and 3) increased P2 permissiveness. The results suggest that the Cys-67 3 Ser mutation weakens B pocket interactions, leading to decreased stability of the mutant-peptide complexes. This may be partially compensated by interactions involving bulky P1 residues. The effect of the mutation on allorecognition was consistent with that on peptide specificity. Our results may aid understanding of the pathogenetic role of HLA-B27 in spondyloarthropathy.

show abstract

“…Subsequent studies confirmed that an HLA-B27-derived peptide, closely related to the predicted one, B27-(169 -179), was a natural ligand of HLA-B27 (24,25). However, this peptide was abundant in the endogenous peptide pools from both disease-associated and non-associated subtypes, which questioned its pathogenetic relevance.…”

mentioning

confidence: 97%

Molecular Mimicry of an HLA-B27-derived Ligand of Arthritis-linked Subtypes with Chlamydial Proteins

Ramos¹,

Álvarez²,

Sesma³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Differences in endogenous peptides presented by HLA-B2705 and B2703 allelic variants. Implications for susceptibility to spondylarthropathies.

Cited by 58 publications

References 41 publications

Peptide Handling by HLA-B27 Subtypes Influences Their Biological Behavior, Association with Ankylosing Spondylitis and Susceptibility to Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

Peptide Handling by HLA-B27 Subtypes Influences Their Biological Behavior, Association with Ankylosing Spondylitis and Susceptibility to Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

The Cys-67 Residue of HLA-B27 Influences Cell Surface Stability, Peptide Specificity, and T-cell Antigen Presentation

Molecular Mimicry of an HLA-B27-derived Ligand of Arthritis-linked Subtypes with Chlamydial Proteins

Contact Info

Product

Resources

About