3qxd Citations

Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange.

Proc. Natl. Acad. Sci. U.S.A. 108 19329-34 (2011)
Cited: 29 times
EuropePMC logo PMID: 22084083


HLA-DM is required for efficient peptide exchange on class II MHC molecules, but its mechanism of action is controversial. We trapped an intermediate state of class II MHC HLA-DR1 by substitution of αF54, resulting in a protein with increased HLA-DM binding affinity, weakened MHC-peptide hydrogen bonding as measured by hydrogen-deuterium exchange mass spectrometry, and increased susceptibility to DM-mediated peptide exchange. Structural analysis revealed a set of concerted conformational alterations at the N-terminal end of the peptide-binding site. These results suggest that interaction with HLA-DM is driven by a conformational change of the MHC II protein in the region of the α-subunit 3(10) helix and adjacent extended strand region, and provide a model for the mechanism of DM-mediated peptide exchange.

Reviews citing this publication (9)

Articles citing this publication (20)

  1. Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection. Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, Pyrdol J, Wucherpfennig KW. Cell 151 1557-1568 (2012)
  2. 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. Yin L, Calvo-Calle JM, Dominguez-Amorocho O, Stern LJ. J. Immunol. 189 3983-3994 (2012)
  3. Comprehensive analysis of MHC class II genes in teleost fish genomes reveals dispensability of the peptide-loading DM system in a large part of vertebrates. Dijkstra JM, Grimholt U, Leong J, Koop BF, Hashimoto K. BMC Evol. Biol. 13 260 (2013)
  4. Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition. Hawse WF, Gloor BE, Ayres CM, Kho K, Nuter E, Baker BM. J. Biol. Chem. 288 24372-24381 (2013)
  5. A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing. Ferrante A, Gorski J. Sci Rep 2 386 (2012)
  6. Selector function of MHC I molecules is determined by protein plasticity. Bailey A, Dalchau N, Carter R, Emmott S, Phillips A, Werner JM, Elliott T. Sci Rep 5 14928 (2015)
  7. Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide. Yin L, Trenh P, Guce A, Wieczorek M, Lange S, Sticht J, Jiang W, Bylsma M, Mellins ED, Freund C, Stern LJ. J. Biol. Chem. 289 23449-23464 (2014)
  8. Re-Directing CD4(+) T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough. Holland CJ, Cole DK, Godkin A. Front Immunol 4 172 (2013)
  9. Structural and dynamical insights on HLA-DR2 complexes that confer susceptibility to multiple sclerosis in Sardinia: a molecular dynamics simulation study. Kumar A, Cocco E, Atzori L, Marrosu MG, Pieroni E. PLoS ONE 8 e59711 (2013)
  10. HLA-DO as the optimizer of epitope selection for MHC class II antigen presentation. Poluektov YO, Kim A, Hartman IZ, Sadegh-Nasseri S. PLoS ONE 8 e71228 (2013)
  11. HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. Meza-Romero R, Benedek G, Yu X, Mooney JL, Dahan R, Duvshani N, Bucala R, Offner H, Reiter Y, Burrows GG, Vandenbark AA. J. Immunol. 192 4164-4173 (2014)
  12. Defining molecular signature of pro-immunogenic radiotherapy targets in human prostate cancer cells. Aryankalayil MJ, Makinde AY, Gameiro SR, Hodge JW, Rivera-Solis PP, Palayoor ST, Ahmed MM, Coleman CN. Radiat. Res. 182 139-148 (2014)
  13. 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. Schulze MS, Anders AK, Sethi DK, Call MJ. PLoS ONE 8 e69228 (2013)
  14. MHC class II complexes sample intermediate states along the peptide exchange pathway. Wieczorek M, Sticht J, Stolzenberg S, Günther S, Wehmeyer C, El Habre Z, Álvaro-Benito M, Noé F, Freund C. Nat Commun 7 13224 (2016)
  15. The Thermodynamic Mechanism of Peptide-MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM. Ferrante A, Templeton M, Hoffman M, Castellini MJ. J. Immunol. 195 1251-1261 (2015)
  16. Evaluating the Role of HLA-DM in MHC Class II-Peptide Association Reactions. Yin L, Maben ZJ, Becerra A, Stern LJ. J. Immunol. 195 706-716 (2015)
  17. 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. Yin L, Stern LJ. J. Immunol. Methods 406 21-33 (2014)
  18. Single-molecule motions of MHC class II rely on bound peptides. Kozono H, Matsushita Y, Ogawa N, Kozono Y, Miyabe T, Sekiguchi H, Ichiyanagi K, Okimoto N, Taiji M, Kanagawa O, Sasaki YC. Biophys. J. 108 350-359 (2015)
  19. Peptidomic analysis of type 1 diabetes associated HLA-DQ molecules and the impact of HLA-DM on peptide repertoire editing. Zhou Z, Reyes-Vargas E, Escobar H, Chang KY, Barker AP, Rockwood AL, Delgado JC, He X, Jensen PE. Eur. J. Immunol. 47 314-326 (2017)
  20. Efficient estimation of binding free energies between peptides and an MHC class II molecule using coarse-grained molecular dynamics simulations with a weighted histogram analysis method. Huang M, Huang W, Wen F, Larson RG. J Comput Chem 38 2007-2019 (2017)