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

Ferrante, Andrea; Templeton, Megan; Hoffman, Megan; Castellini, Margaret J.

doi:10.4049/jimmunol.1402367

Cited by 22 publications

(26 citation statements)

References 56 publications

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“…5), demonstrating that distal interactions can influence the energetic contributions of remote structural elements in the catalytic intermediate. This observation is consistent with studies suggesting that the global conformational state of the pMHCII is a determinant of DM susceptibility (20,28,43,44,55). This notion was exemplified by interactions involving the peptide C terminus that resulted in a significant impact to DM-binding affinity.…”

Section: Dm Senses Pmhcii Interactions Throughout the Binding Cleftsupporting

confidence: 90%

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HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

Reyes-Vargas

Barker

Zhou

et al. 2020

Journal of Biological Chemistry

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Human leukocyte antigen-DM (HLA-DM) is an integral component of the major histocompatibility complex class II (MHCII) antigen-processing and -presentation pathway. HLA-DM shapes the immune system by differentially catalyzing peptide exchange on MHCII molecules, thereby editing the peptide-MHCII (pMHCII) repertoire by imposing a bias on the foreign and self-derived peptide cargos that are presented on the cell surface for immune surveillance and tolerance induction by CD4+ T cells. To better understand DM selectivity, here we developed a real-time fluorescence anisotropy assay to delineate the pMHCII intrinsic stability, DM-binding affinity, and catalytic turnover, independent kinetic parameters of HLA-DM enzymatic activity. We analyzed prominent pMHCII contacts by differentiating the kinetic parameters in pMHCII homologs, observing that peptide interactions throughout the MHCII-binding cleft influence both the rate of peptide dissociation from the DM-pMHCII catalytic complex and the binding affinity of HLA-DM for a pMHCII. We show that the intrinsic stability of a pMHCII linearly correlates with DM catalytic turnover, but is nonlinearly correlated with its binding affinity. Surprisingly, interactions at the peptides N terminus up to and including MHCII position one (P1) anchor affected the catalytic turnover, suggesting that the active DM-pMHCII catalytic complex operates on pMHCII complexes with full peptide occupancy. Furthermore, interactions at the peptide C terminus modulated DM-binding affinity, suggesting distal communication between peptide interactions with the MHCII and the DM-pMHCII binding interface. Our results imply an intimate linkage between the DM-pMHCII interface and peptide-MHCII interactions throughout the peptide-binding cleft.

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Section: Dm Senses Pmhcii Interactions Throughout the Binding Cleftsupporting

confidence: 90%

“…Other studies, however, have suggested that DM susceptibility may not be entirely determined by disruptions at the peptide's N terminus. Rather, DM susceptibility may be governed by the global conformational state of the pMHCII (20,28,43,44).…”

mentioning

confidence: 99%

HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

Reyes-Vargas

Barker

Zhou

et al. 2020

Journal of Biological Chemistry

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show abstract

“…Conformational plasticity has long been suspected to lie at the heart of recapitulating antigen exchange at the molecular level13212730313233. Comparing the wealth of solved MHCII-peptide structures hinted at structural variability that might well extend beyond the ground-state structures seen so far181922.…”

Section: Discussionmentioning

confidence: 99%

“…4g). Thus, in the context of a low-affinity peptide we would anticipate that destabilizing mutations or polymorphisms have an additive effect and that enthalpic and entropic contributions from the entire pMHCII system determine the DM susceptibility of an individual pMHCII (refs 27, 33). …”

Section: Discussionmentioning

confidence: 99%

MHC class II complexes sample intermediate states along the peptide exchange pathway

Wieczorek

Sticht

Stolzenberg³

et al. 2016

Nat Commun

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The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII's ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual's MHC restricted immune response.

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“…38 Studies in similar biological systems show that the simulation time reported here is adequate for the conformational analysis of the bound epitope. [46][47][48][49][50] The parameters for the proteins and the peptide were constructed using the AMBER ff14SB 9 force field. 39 The next step involved the minimization of the system followed by the heating of the complex to 300 K for 100 ps.…”

Section: Molecular Dynamics (Md) Simulation Of Tcr-hmog35-55-hla Dr2 mentioning

confidence: 99%

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

Yannakakis

Tzoupis

Michailidou

et al. 2016

Journal of Molecular Graphics and Modelling

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Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction. The immunodominant 35-55 epitope of MOG is widely used for in vivo biological evaluation and immunological studies that are related with chronic Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS), inflammatory diseases and MS. In this report, Molecular Dynamics (MD) simulations were used to explore the interactions of MOG35-55 at the receptor level. A detailed mapping of the developed interactions during the creation of the trimolecular complex is reported. This is the first attempt to gain an understanding of the molecular recognition of the MOG35-55 epitope by the HLA and TCR receptors. During the formation of the trimolecular complex, the residues Arg(41) and Arg(46) of MOG35-55 have been confirmed to serve as TCR anchors while Tyr(40) interacts with HLA. The present structural findings indicate that the Arg at positions 41 and 46 is a key residue for the stimulation of the encephalitogenic T-cells.

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

Cited by 22 publications

References 56 publications

HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

MHC class II complexes sample intermediate states along the peptide exchange pathway

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

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