Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide*

Background: HLA-DM-mediated peptide exchange is a key factor in epitope selection, but how HLA-DM selects peptides for editing is not known. Results: Peptide complexes sensitive to HLA-DM editing exhibited conformational alterations. Conclusion: HLA-DM efficiently identifies unstable complexes by sensing MHCII-peptide conformations. Significance: These data emphasize HLA-DM as a conformational editor and provide novel mechanistic insight into its function. HLA-DM mediates the exchange of peptides loaded onto MHCII molecules during antigen presentation by a mechanism that remains unclear and controversial. Here, we investigated the sequence and structural determinants of HLA-DM interaction. Peptides interacting nonoptimally in the P1 pocket exhibited low MHCII binding affinity and kinetic instability and were highly susceptible to HLA-DM-mediated peptide exchange. These changes were accompanied by conformational alterations detected by surface plasmon resonance, SDS resistance assay, antibody binding assay, gel filtration, dynamic light scattering, small angle x-ray scattering, and NMR spectroscopy. Surprisingly, all of those changes could be reversed by substitution of the P9 pocket anchor residue. Moreover, MHCII mutations outside the P1 pocket and the HLA-DM interaction site increased HLA-DM susceptibility. These results indicate that a dynamic MHCII conformational determinant rather than P1 pocket occupancy is the key factor determining susceptibility to HLA-DM-mediated peptide exchange and provide a molecular mechanism for HLA-DM to efficiently target unstable MHCII-peptide complexes for editing and exchange those for more stable ones.

• Publication year

  2014

• Venue

  Journal of Biological Chemistry

• Publication date

  2014-07-07

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M114.585539PMID 25002586PMCID PMC4156084
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination.

  2014cited by this paper
• A novel pathway of presentation by class II-MHC molecules involving peptides or denatured proteins important in autoimmunity.

  2013cited by this paper
• HLA‐DM: arbiter conformationis

  2013cited by this paper
• HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange

  2013cited by this paper
• Disruption of Hydrogen Bonds between Major Histocompatibility Complex Class II and the Peptide N-Terminus Is Not Sufficient to Form a Human Leukocyte Antigen-DM Receptive State of Major Histocompatibility Complex Class II

  2013cited by this paper
• Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection.

  2012cited by this paper
• HLA-DM Constrains Epitope Selection in the Human CD4 T Cell Response to Vaccinia Virus by Favoring the Presentation of Peptides with Longer HLA-DM–Mediated Half-Lives

  2012cited by this paper
• A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing

  2012cited by this paper
• Peptide linkage to the α-subunit of MHCII creates a stably inverted antigen presentation complex.

  2012cited by this paper
• Endogenous HLA class II epitopes that are immunogenic in vivo show distinct behavior toward HLA-DM and its natural inhibitor HLA-DO.

  2012cited by this paper
• Conformational variation in structures of classical and non‐classical MHCII proteins and functional implications

  2012cited by this paper
• HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism

  2012cited by this paper
• The mechanism of HLA-DM induced peptide exchange in the MHC class II antigen presentation pathway.

  2012cited by this paper
• T Lymphocyte Responses to Nonpolymorphic HLA-Derived Peptides Are Associated With Chronic Renal Allograft Dysfunction

  2011cited by this paper
• Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange

  2011cited by this paper
• An Insertion Mutant in DQA1*0501 Restores Susceptibility to HLA-DM: Implications for Disease Associations

  2011cited by this paper
• Bidirectional binding of invariant chain peptides to an MHC class II molecule

  2010cited by this paper
• A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes

  2010cited by this paper
• HLA-DM Captures Partially Empty HLA-DR Molecules for Catalyzed Peptide Removal

  2010cited by this paper
• FoXS: a web server for rapid computation and fitting of SAXS profiles

  2010cited by this paper
• Conformational heterogeneity of MHC class II induced upon binding to different peptides is a key regulator in antigen presentation and epitope selection

  2010cited by this paper
• Complexes of two cohorts of CLIP peptides and HLA-DQ2 of the autoimmune DR3-DQ2 haplotype are poor substrates for HLA-DM

  2009cited by this paper
• Cutting Edge: HLA-DM Functions through a Mechanism That Does Not Require Specific Conserved Hydrogen Bonds in Class II MHC-Peptide Complexes1

  2009cited by this paper
• Cutting Edge: HLA-DM–Mediated Peptide Exchange Functions Normally on MHC Class II–Peptide Complexes That Have Been Weakened by Elimination of a Conserved Hydrogen Bond

  2009cited by this paper
• The role of dynamic conformational ensembles in biomolecular recognition.

  2009cited by this paper
• HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1.

  2009cited by this paper
• HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

  2008cited by this paper
• Human monoclonal antibody with T-cell-like specificity recognizes MHC class I self-peptide presented by HLA-DR1 on activated cells.

  2008cited by this paper
• HLA-DM Mediates Epitope Selection by a “Compare-Exchange” Mechanism when a Potential Peptide Pool Is Available

  2008cited by this paper
• Model for the Peptide-Free Conformation of Class II MHC Proteins

  2008cited by this paper
• Complexes of Two Cohorts of CLIP Peptides and HLA-DQ2 of the Autoimmune DR3-DQ2 Haplotype Are Poor Substrates for HLA-DM1

  2008cited by this paper
• Indirect recognition of T-cell epitopes derived from the alpha 3 and transmembrane domain of HLA-A2.

  2007cited by this paper
• Indirect Recognition of T‐Cell Epitopes Derived from the α3 and Transmembrane Domain of HLA‐A2

  2007cited by this paper
• HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR–peptide complexes

  2007cited by this paper
• Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process1

  2007cited by this paper
• The impact of DM on MHC class II–restricted antigen presentation can be altered by manipulation of MHC–peptide kinetic stability

  2006cited by this paper
• The relationship between immunodominance, DM editing, and the kinetic stability of MHC class II:peptide complexes

  2005cited by this paper
• The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance.

  2005cited by this paper
• The CCPN data model for NMR spectroscopy: Development of a software pipeline

  2005cited by this paper
• Cooperativity during the formation of peptide/MHC class II complexes.

  2005cited by this paper
• Monoclonal Antibodies Specific for the Empty Conformation of HLA-DR1 Reveal Aspects of the Conformational Change Associated with Peptide Binding*

  2004cited by this paper
• Enhanced Catalytic Action of HLA-DM on the Exchange of Peptides Lacking Backbone Hydrogen Bonds between their N-Terminal Region and the MHC Class II α-Chain1

  2004cited by this paper
• T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM.

  2004cited by this paper
• Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

  2004cited by this paper
• Point Mutations in or Near the Antigen-Binding Groove of HLA-DR3 Implicate Class II-Associated Invariant Chain Peptide Affinity as a Constraint on MHC Class II Polymorphism1

  2003cited by this paper
• Looking behind the beamstop: X-ray solution scattering studies of structure and conformational changes of biological macromolecules.

  2003cited by this paper
• Small-angle scattering studies of biological macromolecules in solution

  2003cited by this paper
• PRIMUS: a Windows PC-based system for small-angle scattering data analysis

  2003cited by this paper
• Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing 1

  2003cited by this paper
• Structural Factors Contributing to DM Susceptibility of MHC Class II/Peptide Complexes1

  2002cited by this paper
• Distinct recognition by two subsets of T cells of an MHC class II-peptide complex

  2002cited by this paper
• Relationship between kinetic stability and immunogenicity of HLA‐DR4/peptide complexes

  2002cited by this paper
• Hla-Dm Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II

  2000cited by this paper
• Dm Determines the Cryptic and Immunodominant Fate of T Cell Epitopes

  2000cited by this paper
• Determinants of the Peptide-induced Conformational Change in the Human Class II Major Histocompatibility Complex Protein HLA-DR1*

  2000cited by this paper
• A three-step kinetic mechanism for peptide binding to MHC class II proteins.

  2000cited by this paper
• Empty and peptide-loaded class II major histocompatibility complex proteins produced by expression in Escherichia coli and folding in vitro.

  1999cited by this paper
• Sodium dodecyl sulfate stability of HLA-DR1 complexes correlates with burial of hydrophobic residues in pocket 1.

  1999cited by this paper
• A conformational change in the human major histocompatibility complex protein HLA-DR1 induced by peptide binding.

  1999cited by this paper
• Aberrant intermolecular disulfide bonding in a mutant HLA-DM molecule: implications for assembly, maturation, and function.

  1998cited by this paper
• The class II MHC protein HLA-DR1 in complex with an endogenous peptide: implications for the structural basis of the specificity of peptide binding.

  1997cited by this paper
• Editing of the HLA‐DR‐peptide repertoire by HLA‐DM.

  1996cited by this paper
• Enhanced Dissociation of HLA-DR-Bound Peptides in the Presence of HLA-DM

  1996cited by this paper
• Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II-like conformation for bound peptides.

  1996cited by this paper
• Mediation by HLA-DM of dissociation of peptides from HLA-DR

  1995cited by this paper
• HLA-DR alpha chain residues located on the outer loops are involved in nonpolymorphic and polymorphic antibody-binding epitopes.

  1994cited by this paper
• MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation.

  1994cited by this paper
• Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide

  1994cited by this paper
• An essential role for HLA–DM in antigen presentation by class II major histocompatibility molecules

  1994cited by this paper
• Promiscuous and allele-specific anchors in HLA-DR-binding peptides.

  1993cited by this paper
• Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size

  1992cited by this paper
• The human class II MHC protein HLA-DR1 assembles as empty αβ heterodimers in the absence of antigenic peptide

  1992cited by this paper
• The human class II MHC protein HLA-DR1 assembles as empty alpha beta heterodimers in the absence of antigenic peptide.

  1992cited by this paper
• High-affinity binding of an influenza hemagglutinin-derived peptide to purified HLA-DR.

  1990cited by this paper
• MHC class II-associated invariant chain contains a sorting signal for endosomal compartments.

  1990cited by this paper
• Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding

  1990cited by this paper
• Direct method of interpretation of small-angle scattering by the solutions of biological macromolecules

  1982cited by this paper
• Small-angle scattering. Information content and error analysis

  1980cited by this paper

• HLA‐DRB1 Allelic Combinations Differentially Shape Dendritic Cell Antigen Presentation Enhanced by Tumour Cell Line Lysate‐Pulsing

  2026cites this paper
• Expression and Functional Characterization of Recombinant HLA-DM.

  2026cites this paper
• Differential pairing of transmembrane domain GxxxG dimerization motifs defines two HLA-DR MHC class II conformers

  2023cites this paper
• MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange

  2023influential citation
• HLA-II immunopeptidome profiling and deep learning reveal features of antigenicity to inform antigen discovery.

  2023cites this paper
• Journal Pre-proof Loading dynamics of one SARS-CoV-2-derived peptide into MHC-II revealed by kinetic models

  2023cites this paper
• Structural Framework for Analysis of CD4+ T-Cell Epitope Dominance in Viral Fusion Proteins

  2023cites this paper
• An immunoinformatic approach to assessing the immunogenic capacity of alpha-neurotoxins in elapid snake venoms

  2023cites this paper
• Loading dynamics of one SARS-CoV-2-derived peptide into MHC-II revealed by kinetic models

  2023cites this paper
• The mode of action of tapasin on major histocompatibility class I (MHC-I) molecules

  2023cites this paper
• A previously unappreciated polymorphism in the beta chain of I-As expressed in autoimmunity-prone SJL mice: Combined impact on antibody, CD4 T cell recognition and MHC class II dimer structural stability.

  2022cites this paper
• Peptide-dependent tuning of major histocompatibility complex motional properties and the consequences for cellular immunity.

  2022cites this paper
• Regulation of the BCR signalosome by the class II peptide editor, H2-M, affects the development and repertoire of innate-like B cells.

  2022cites this paper
• Design of a Novel Multi-Epitope Vaccine Against Echinococcus granulosus in Immunoinformatics

  2021cites this paper
• Partnering for the major histocompatibility complex class II and antigenic determinant requires flexibility and chaperons.

  2021cites this paper
• Major histocompatibility complex (MHC) class I and class II proteins: impact of polymorphism on antigen presentation.

  2021cites this paper
• CD74, a novel predictor for bronchopulmonary dysplasia in preterm infants

  2020cites this paper
• HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

  2020influential citation
• The love and hate relationship of HLA-DM/DO in the selection of immunodominant epitopes.

  2020cites this paper
• Revisiting nonclassical HLA II functions in antigen presentation: Peptide editing and its modulation

  2020cites this paper
• Repertoire-scale determination of class II MHC peptide binding via yeast display improves antigen prediction

  2020cites this paper
• Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition

  2020cites this paper
• ImmunoPhysics and ImmunoEngineering

  2020cites this paper
• Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides

  2020cites this paper
• The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

  2019cites this paper
• Association between HCV infection and the incidence of Diabetes Mellitus in Egyptians

  2019cites this paper
• Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning

  2019cites this paper
• The TCR/peptide/MHC complex with a superagonist peptide shows similar interface and reduced flexibility compared to the complex with a self-peptide

  2019cites this paper
• What to do with HLA-DO/H-2O two decades later?

  2019cites this paper
• Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

  2019cites this paper
• Studies in Antigen Presentation and Antigen Recognition at Different Interfaces of the Adaptive Immune System

  2018influential citation
• Previously Hidden Dynamics at the TCR–Peptide–MHC Interface Revealed

  2018cites this paper
• The N-terminal region of photocleavable peptides that bind HLA-DR1 determines the kinetics of fragment release

  2018cites this paper
• Class II MHC antigen processing in immune tolerance and inflammation

  2018cites this paper
• Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

  2018cites this paper
• HLA-DO Modulates the Diversity of the MHC-II Self-peptidome*

  2018influential citation
• Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-associated invariant chain peptides

  2017cites this paper
• Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation

  2017cites this paper
• Peptidomic analysis of type 1 diabetes associated HLA‐DQ molecules and the impact of HLA‐DM on peptide repertoire editing

  2017cites this paper
• Ligand Selection and Trafficking for MHC II

  2016cites this paper
• A step-by-step overview of the dynamic process of epitope selection by major histocompatibility complex class II for presentation to helper T cells

  2016cites this paper
• The Forgotten: Identification and Functional Characterization of MHC Class II Molecules H2-Eb2 and RT1-Db2

  2016cites this paper
• MHC class II complexes sample intermediate states along the peptide exchange pathway

  2016cites this paper
• Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

  2016cites this paper
• Structure of Classical MHCII (HLA-DP, DQ, DR, and Orthologs)

  2016cites this paper
• Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide-MHC complexes.

  2016influential citation
• The melting pot of the MHC II peptidome.

  2016cites this paper
• Cell Tumors Mediated Immune Recognition of Human B - Elevation of c-MYC Disrupts HLA Class II

  2015cites this paper
• Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

  2015cites this paper
• The Thermodynamic Mechanism of Peptide–MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM

  2015cites this paper
• The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling

  2015cites this paper
• The Thermodynamic Mechanism of Peptide

  2015cites this paper
• Peptide Association Reactions - Class II Evaluating the Role of HLA-DM in MHC

  2015cites this paper
• Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions

  2015cites this paper
• Determinant of Susceptibility to HLA-DM MHC Class II Complex Formation Is a − The Thermodynamic Mechanism of Peptide

  2015cites this paper
• Determinants of immunodominance for CD4 T cells.

  2015cites this paper
• Selector function of MHC I molecules is determined by protein plasticity

  2015cites this paper