Analysis of the structure of empty and peptide-loaded major histocompatibility complex molecules at the cell surface.

Catipovic, Branimir; Talluri, G.; Oh, Jason Z.; Wei, Taiyin; Su, Xiaomin; Johansen, Teit E.; Edidin, Michael; Schneck, Jonathan P.

doi:10.1084/jem.180.5.1753

Cited by 33 publications

(18 citation statements)

References 46 publications

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“…7), seems to be crucial for the HC-10-defined epitope expression. It is reasonable to speculate that the peptide 55-64 including the mAb HC-10-defined motif, is in a more extended conformation on the ␤ 2 m-free HC (31). Transfer of the mAb HC-10 epitope using mutagenesis to convert a nonreactive allele to a reactive one will be useful to address these points and to support HC-10-epitope definition in relation to conformational changes occurring when peptide and/or ␤ 2 m bind or dissociate (29).…”

Section: Discussionmentioning

confidence: 99%

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

Perosa

Luccarelli

Prete

et al. 2003

The Journal of Immunology

150

163

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mAb HC-10 loses its reactivity with HLA class I (HLA-I) H chain (HC) following its association with β2-microglobulin (β2m). Furthermore, the HC-10 defined epitope appears to be involved in the pathogenesis of spondyloarthropathies, because HC-10 reduced their incidence in HLA-B27+β2m°/MHC class II knockout mice. This study has characterized the determinant recognized by HC-10. Panning of a phage display peptide library with HC-10 resulted in isolation of the motif PxxWDR, which could be aligned with P57, W60, D61, and R62 of the first domain of the HLA-I HC allospecificities reactive with HC-10. The 55EGPEYWDR(N/E)T64 (p-1) is the shortest motif-bearing peptide that reacts with HC-10 and inhibits its binding to soluble HLA-B7 HC, irrespective of whether N (p-1a) or E (p-1b) is present at position 63. By contrast, HC-10 did not react with six additional peptides, each bearing motif amino acid substitutions present in HC-10-not-reactive HLA-I allospecificities. The p-1-derived Qp-1, synthesized with the additional conserved Q54, which displays the highest in vitro reactivity with HC-10, was the only one to induce in mice IgG resembling HC-10 in their fine specificity. Mapping of the HC-10-defined determinant suggests that the lack of mAb reactivity with β2m-associated HLA-I HC is caused by blocking by the peptide in the groove of β2m-associated HLA-I HC, though a role of HC conformational changes following its association with β2m cannot be excluded. This information contributes to our understanding of the molecular basis of the antigenic profiles of β2m-free and β2m-associated HLA-I HC and may serve to develop active specific immunotherapy of spondyloarthropathies.

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Section: Discussionmentioning

confidence: 99%

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

Perosa

Luccarelli

Prete

et al. 2003

The Journal of Immunology

150

163

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“…While this term must always be present, its magnitude is difficult to estimate. In fact, no peptide-free MHC class I protein crystal structure has been reported to date, so that only indirect evidence is available as to the protein structural changes that accompany peptide binding (Elliott et al, 1991;Bluestone et al, , 1993Catipovic et al, 1992Catipovic et al, , 1994Sherman et al, 1993;Rohren et al, 1994). However, they are likely to be similar for the same protein interacting with different peptides, which is consistent with the fact that the protein conformation of both H-2Kb and HLA-A2 shows only minor conformational changes in comparing one protein-peptide complex to another (Fremont et al, 1992(Fremont et al, , 1995Madden et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions

1997

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This paper describes a methodology to calculate the binding free energy (AG) of a protein-ligand complex using a continuum model of the solvent. A formal thermodynamic cycle is used to decompose the binding free energy into electrostatic and non-electrostatic contributions. In this cycle, the reactants are discharged in water, associated as purely nonpolar entities, and the final complex is then recharged. The total electrostatic free energies of the protein, the ligand, and the complex in water are calculated with the finite difference Poisson-Boltzmann (FDPB) method. The nonpolar (hydrophobic) binding free energy is calculated using a free energy-surface area relationship, with a single alkane/water surface tension coefficient (yaw). The loss in backbone and side-chain configurational entropy upon binding is estimated and added to the electrostatic and the nonpolar components of AG. The methodology is applied to the binding of the murine MHC class I protein H-2Kb with three distinct peptides, and to the human MHC class I protein HLA-A2 in complex with five different peptides. Despite significant differences in the amino acid sequences of the different peptides, the experimental binding free energy differences (AAGexp) are quite small (<0.3 and <2.7 kcal/mol for the H-2Kb and HLA-A2 complexes, respectively). For each protein, the calculations are successful in reproducing a fairly small range of values for AAGCalc (<4.4 and <5.2 kcal/mol, respectively) although the relative peptide binding affinities of H-2Kb and HLA-A2 are not reproduced. For all protein-peptide complexes that were treated, it was found that electrostatic interactions oppose binding whereas nonpolar interactions drive complex formation. The two types of interactions appear to be correlated in that larger nonpolar contributions to binding are generally opposed by increased electrostatic contributions favoring dissociation. The factors that drive the binding of peptides to MHC proteins are discussed in light of our results. and AGs,,lv); AG.,, nonpolar (hydrophobic) contribution to binding; AG,,,,,, change in conformational free energy of both the receptor and the ligand upon binding; AS,, and AS,, loss of configurational entropy due to the freezing of backbone and side-chain torsional angles upon binding; A&, loss of translational and rotational degrees of freedom upon binding; A, solvent-accessible surface area; yaw, microscopic surface tension associated with the transfer of alkane from liquid alkane to water: E,, dielectric constant of water; 6 , dielectric constant of macromolecular interior. KeywordsThe accurate calculation of ligand-protein binding free energies is a difficult problem for which no general solution has been forthcoming. Molecular dynamics simulations including the explicit treatment of solvent molecules have encountered a number of striking successes (see, e.g., Bash et al

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“…EL-4 is a T-cell thymoma syngeneic to B6 mice. RMAS cells are TAP-deficient cells that are defective in transporters associated with antigen processing and express functionally "empty" class I major histocompatibility complex molecules on the cell surface (20).…”

Section: Methodsmentioning

confidence: 99%

Anti-CD137 Monoclonal Antibody Administration Augments the Antitumor Efficacy of Dendritic Cell-Based Vaccines

et al. 2004

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Analysis of the structure of empty and peptide-loaded major histocompatibility complex molecules at the cell surface.

Cited by 33 publications

References 46 publications

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions

Anti-CD137 Monoclonal Antibody Administration Augments the Antitumor Efficacy of Dendritic Cell-Based Vaccines

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