Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions that Bind Peptides to MHC Class II Protein

McFarland, Benjamin J.; Katz, John F.; Sant, Andrea J.; Beeson, Craig C.

doi:10.1016/j.jmb.2005.04.069

Cited by 43 publications

(40 citation statements)

References 87 publications

(131 reference statements)

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“…We extended these observations to include the effect of changing a side chain involved in a weak hydrophobic anchoring at P7, indicating that in addition this energetic source can contribute to cooperativity (15). Similar studies performed on peptide/I-A d complexes revealed that the energetic contribution of a given anchor-pocket pair depends on the overall peptide sequence, suggesting coupling to directly adjacent residues (16). However, more detailed investigations would be required to relate cooperativity to the folding process and its effect on the epitope selection.…”

Section: T He Mhc Class II (Mhcii)supporting

confidence: 53%

“…Moreover, our findings may not be valid for all allelic and isotypic forms of MHCII. For instance, a recent study, investigating the energetics of the peptide/I-A d complex, showed that the contribution of a given anchor-pocket pair in binding depends on the overall peptide sequence, but no evidence for cooperativity between anchor residue interactions and H-bonds was detected, independent of the distance (16). It should be pointed out that I-A d may depend less on strong pocket interactions, relying to an atypically high degree on Hbonding interactions (35).…”

Section: Discussionmentioning

confidence: 99%

“…A previous report has showed no evidence of cooperativity between anchors and adjacent H-bonds for peptide/I-A d complexes, suggesting that a certain amount of additivity is inherent to peptide binding (16). We asked whether in our model, simultaneous substitution at positions with intermediate solvent accessibility and positions involved in hydrophobic interactions could result in a cooperative effect.…”

Section: Contribution Of Simultaneous Substitution At Low and Intermementioning

confidence: 97%

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Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Ferrante

Gorski

2007

The Journal of Immunology

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Peptide binding to MHC class II (MHCII) molecules is stabilized by hydrophobic anchoring and hydrogen bond formation. We view peptide binding as a process in which the peptide folds into the binding groove and to some extent the groove folds around the peptide. Our previous observation of cooperativity when analyzing binding properties of peptides modified at side chains with medium to high solvent accessibility is compatible with such a view. However, a large component of peptide binding is mediated by residues with strong hydrophobic interactions that bind to their respective pockets. If these reflect initial nucleation events they may be upstream of the folding process and not show cooperativity. To test whether the folding hypothesis extends to these anchor interactions, we measured dissociation and affinity to HLA-DR1 of an influenza hemagglutinin-derived peptide with multiple substitutions at major anchor residues. Our results show both negative and positive cooperative effects between hydrophobic pocket interactions. Cooperativity was also observed between hydrophobic pockets and positions with intermediate solvent accessibility, indicating that hydrophobic interactions participate in the overall folding process. These findings point out that predicting the binding potential of epitopes cannot assume additive and independent contributions of the interactions between major MHCII pockets and corresponding peptide side chains.

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Section: T He Mhc Class II (Mhcii)supporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Contribution Of Simultaneous Substitution At Low and Intermementioning

confidence: 97%

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Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Ferrante

Gorski

2007

The Journal of Immunology

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“…Peptide binding in the absence of DM is a flexible process, and does not rely on independent contributions from pocket/anchor interactions and H-bonds, but is a function of the synergism involving multiple single-point interactions (30, 31, 39). MHCII molecules feature conformational lability, and the α-subunit 3 10 helical region with the adjacent extended strand, the β2 Ig-like domain, and the pronounced kink in the β-subunit helical region β62-71 are the most subject to conformational heterogeneity, either in the empty or in the bound state (40).…”

Section: Discussionmentioning

confidence: 99%

The Thermodynamic Mechanism of Peptide–MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM

Ferrante

Templeton

Hoffman

et al. 2015

The Journal of Immunology

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Peptides bind Class II Major Histocompatibility Complex molecules (MHCII) through a thermodynamically non-additive process consequent to the flexibility of the reactants. Currently, how the specific outcome of this binding process effects the ensuing epitope selection needs resolution. Calorimetric assessment of binding thermodynamics for HA306-319 peptide variants to the human MHCII HLA-DR1 (DR1) and a mutant DR1 reveals that peptide/DR1 complexes can be formed with different enthalpic and entropic contributions. Complexes formed with a smaller entropic penalty feature circular dichroism spectra consistent with a non-compact form, and molecular dynamics simulation shows a more flexible structure. The opposite binding mode, compact and less flexible, is associated with greater entropic penalty. These structural variations are associated with rearrangements of residues known to be involved in DM binding, affinity of DM for the complex, and complex susceptibility to DM-mediated peptide exchange. Thus, the thermodynamic mechanism of peptide binding to DR1 correlates with the structural rigidity of the complex, and DM mediates peptide exchange by “sensing” flexible complexes in which the aforementioned residues are rearranged at a higher frequency than in more rigid ones.

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“…To address the mechanism of DM effector function on peptide dissociation, we considered altering the hydrogen bonds found between the peptide backbone and conserved amino acids of the MHC class II molecule [33][34][35][36][37] . Published reports have shown that such hydrogen bonds are crucial for peptide-MHC class II complex stability.…”

mentioning

confidence: 99%

HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

et al. 2006

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The peptide editor HLA-DM (DM) mediates exchange of peptides bound to major histocompatibility (MHC) class II molecules during antigen processing; however, the mechanism by which DM displaces peptides remains unclear. Here we generated a soluble mutant HLA-DR1 with a histidine-to-asparagine substitution at position 81 of the β-chain (DR1βH81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide-DR1βH81N complexes dissociated at rates similar to the dissociation rates of DM-induced peptide-wild-type DR1, and DM did not enhance the dissociation of peptide-DR1βH81N complexes. Reintroduction of an appropriate hydrogen bond (DR1βH81N βV85H) restored DM-mediated peptide dissociation. Thus, DR1βH81N might represent a `post-DM effect' conformation. We suggest that DM may mediate peptide dissociation by a `hit-and-run' mechanism that results in conformational changes in MHC class II molecules and disruption of hydrogen bonds between βHis81 and bound peptide.Shortly after being synthesized in the antigen-presenting cell, major histocompatibility complex (MHC) class II αβ heterodimers form nonameric assemblies with invariant chain (Ii) in the endoplasmic reticulum and are then transported through the Golgi complex to the endocytic pathway 1, 2. During transport through the endocytic pathway, most Ii is removed from MHC class II molecules by low pH and acid proteases3, leaving a proteolytic fragment of Ii called `CLIP' bound to MHC class II molecule4. CLIP acts as a `placeholder' for the MHC class II groove, inhibiting conformational changes that render the groove closed5 -13 , and it must be removed to allow binding of exogenous peptides to nascent MHC class II complexes. Human HLA-DM (called `DM' here), or H2-M in mice, is a nonclassical HLA molecule that is critical in the displacement of CLIP 14-17. In addition to displacing CLIP, DM transiently interacts with empty MHC class II molecules to generate a peptide-receptive conformation and is active in the selection of specific peptide-MHC class II complexes during antigen processing18 -26. The two concurrent hypotheses for the recognition of certain peptide-MHC class II by DM relate to the intrinsic affinity between MHC class II © 2006 Nature Publishing Group Correspondence should be addressed to S.S-N (ssadegh@jhmi.edu).. 4 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Immunol. Author manuscript; available in PMC 2011 January 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript and the peptide 22,27,28 or to subtle structural variations among different peptide-MHC complexes 25,[29][30][31][32] , whereby structurally flexible complexes are susceptible to DM-induced dissociation, and `rigid' complexes are resistant to DM 25 . Although those studies may have brought greater understanding of the crite...

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Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions that Bind Peptides to MHC Class II Protein

Cited by 43 publications

References 87 publications

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

The Thermodynamic Mechanism of Peptide–MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM

HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

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