Thermodynamic and Structural Equivalence of Two HLA-B27 Subtypes Complexed with a Self-peptide

Hülsmeyer, Martin; Welfle, Karin; Pöhlmann, Thomas; Misselwitz, Rolf; Alexiev, Ulrike; Welfle, Heinz; Saenger, Wolfram; Uchańska-Ziegler, Barbara; Ziegler, Andreas

doi:10.1016/j.jmb.2004.12.047

Cited by 49 publications

(64 citation statements)

References 59 publications

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“…Alternatively, peptides that are endogenously loaded onto the empty MHC class I with the assistance of a specialized multimeric unit called the peptide-loading complex (47,48) in the endoplasmic reticulum could have conformational characteristics different from those of molecules refolded in vitro. More importantly, the RY11/HLA-B35 complex showed two relatively simple two-state transitions in thermal unfolding, in which a high-temperature transition corresponds to free ␤ 2 m. Such an unfolding pattern has been reported for various selfpeptides in association with HLA-B27 (36,49). In contrast, the VY8/HLA-B35 complex and two other variant complexes showed significantly interdependent and cooperative unfolding processes among heterotrimer subunits and structural domains, suggesting the critical contribution of ␤ 2 m in maintaining antigenicity of the peptide in association with the H chain.…”

Section: Discussionsupporting

confidence: 52%

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

Motozono

Yanaka

Tsumoto

et al. 2009

The Journal of Immunology

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The antiviral activity of HIV-specific CTL is not equally potent but rather is dependent on their specificity. But what characteristic of targeted peptides influences CTL antiviral activity remains elusive. We addressed this issue based on HLA-B35-restricted CTLs specific for two overlapping immunodominant Nef epitopes, VY8 (VPLRPMTY) and RY11 (RPQVPLRPMTY). VY8-specific CTLs were more potently cytotoxic toward HIV-infected primary CD4+ cells than RY11-specific CTLs. Reconstruction of their TCR revealed no substantial difference in their functional avidity toward cognate Ags. Instead, the decay analysis of the peptide-MHC complex (pMHC) revealed that the VY8/HLA-B35 complex could maintain its capacity to sensitize T cells much longer than its RY11 counterpart. Corroboratively, the introduction of a mutation in the epitopes that substantially delayed pMHC decay rendered Nef-expressing target cells more susceptible to CTL killing. Moreover, by using differential scanning calorimetry and circular dichroism analyses, we found that the susceptible pMHC ligands for CTL killing showed interdependent and cooperative, rather than separate or sequential, transitions within their heterotrimer components under the thermally induced unfolding process. Collectively, our results highlight the significant effects of intrinsic peptide factors that support cooperative thermodynamics within pMHC on the efficient CTL killing of HIV-infected cells, thus providing us better insight into vaccine design.

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Section: Discussionsupporting

confidence: 52%

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

Motozono

Yanaka

Tsumoto

et al. 2009

The Journal of Immunology

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“…3, A and B, respectively. The absorption spectrum of the complexes is characterized by a weak absorption band centered at 428 Ϯ 1 nm for m9, TIS (13,16,18), and gag (data not shown) and 431 Ϯ 2 nm for pVIPR (16), pLMP2 (Fig. 3A), and pGR (data not shown), respectively, which is because of the absorption of the fluorescent label LY attached to the peptide.…”

Section: Resultsmentioning

confidence: 97%

“…Protein Preparation-Complexes of the subtypes B*2705 and B*2709 with the peptides m9, pVIPR, TIS, pLMP2, gag, pGR, and the artificial peptide mutants pVIPR-H8T and pLMP2-T8H were prepared as described previously (10,11,(13)(14)(15)(16)(17)(18)26). The synthetic peptides as well as their fluorescent derivatives labeled with Lucifer Yellow (LY, Molecular Probes) in position C-6 and C-8, respectively, were purchased from Alta Bioscience (Birmingham, UK), Biosynthan (Berlin, Germany), or synthesized in-house.…”

Section: Methodsmentioning

confidence: 99%

“…pK a Analysis-Protein residue pK a calculations were performed on the crystal structures of the two B*2705 and B*2709 subtypes complexed with several different peptides (pLMP2 (14), pVIPR in both canonical (conformation A) and noncanonical (conformation B) conformations (11), TIS (13), and the model peptide m9 (10)). The pK a values were also calculated for the B*2709 subtype complexed with the S10R peptide (12) and for the B*2705 subtype complexed with the pGR peptide presented in two different conformations (pGR A and pGR B (15)).…”

Section: Methodsmentioning

confidence: 99%

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Molecular Determinants of Major Histocompatibility Complex Class I Complex Stability

Narzi

Winkler

Saidowsky

et al. 2008

Journal of Biological Chemistry

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“…Additionally it has been demonstrated in B*27:05 and B*27:09 alleles that the binding of peptides containing a Lys PΩ anchor appears to be weaker and thermodynamically less stable [21]. Such allosteric mechanisms might influence not only the association and dissociation of the trimeric complexes, but also the mode of recognition by the T-cell receptors [22].…”

Section: Discussionmentioning

confidence: 99%

Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

Badrinath¹,

Huyton

Kunze‐Schumacher³

et al. 2014

J Stem Cell Res Ther

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The molecular understanding of how we can mismatch patients and donors and still have successful clinical outcomes will help to guide the future of unrelated bone-marrow transplantation.Single amino acid mismatches at position 156 on the alpha 2 helix of B*44 variants have been described to cause immunological episodes. The magnitude of permissivity between B44/156 variants differs from peptide presentation independent of the peptide loading complex (B*44:28) to influencing clinical episodes (B*44:02 vs. B*44:03). We here investigated if the single exchange of an Asp>Glu as occurring in B*44:35 at residue 156 would force an immune response in vitro.We developed an in vitro system by recombinant co-expression of a single membrane-bound allogeneic HLA class I molecule in donor cells and co-incubating these cells with autologous T-cells. This strategy enables the study of single HLA class I mismatches and excludes the influence of minor antigens. We found these T-cells to be able to differentially discriminate between mismatched B*44 subtypes and their micropolymorphism. To understand how certain pHLA landscapes shaping the alloreactive immune response, we sequenced the individual peptides derived from B*44/156 subtypes using LC-ESI-MS/MS technology. Based on the peptide data we modeled the structure of the B*44:35 variant and can describe the unexpected immunological reaction of the mismatched B*44 subtypes through structural manipulation of the heavy chain.The meticulous characterization of peptide-binding profiles for key alleles, as well as the evaluation of T-cell responses and structural analysis in the context of one-allele mismatches will open the door to a new era in bonemarrow transplantation.

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Thermodynamic and Structural Equivalence of Two HLA-B27 Subtypes Complexed with a Self-peptide

Cited by 49 publications

References 59 publications

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL

Molecular Determinants of Major Histocompatibility Complex Class I Complex Stability

Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

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