4fqx Citations

Crystal Structure of the HLA-DM-HLA-DR1 Complex Defines Mechanisms for Rapid Peptide Selection.


HLA-DR molecules bind microbial peptides in an endosomal compartment and present them on the cell surface for CD4 T cell surveillance. HLA-DM plays a critical role in the endosomal peptide selection process. The structure of the HLA-DM-HLA-DR complex shows major rearrangements of the HLA-DR peptide-binding groove. Flipping of a tryptophan away from the HLA-DR1 P1 pocket enables major conformational changes that position hydrophobic HLA-DR residues into the P1 pocket. These conformational changes accelerate peptide dissociation and stabilize the empty HLA-DR peptide-binding groove. Initially, incoming peptides have access to only part of the HLA-DR groove and need to compete with HLA-DR residues for access to the P2 site and the hydrophobic P1 pocket. This energetic barrier creates a rapid and stringent selection process for the highest-affinity binders. Insertion of peptide residues into the P2 and P1 sites reverses the conformational changes, terminating selection through DM dissociation.

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Reviews citing this publication (21)

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  1. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Gockel I, Becker J, Wouters MM, Niebisch S, Gockel HR, Hess T, Ramonet D, Zimmermann J, Vigo AG, Trynka G, de León AR, de la Serna JP, Urcelay E, Kumar V, Franke L, Westra HJ, Drescher D, Kneist W, Marquardt JU, Galle PR, Mattheisen M, Annese V, Latiano A, Fumagalli U, Laghi L, Cuomo R, Sarnelli G, Müller M, Eckardt AJ, Tack J, Hoffmann P, Herms S, Mangold E, Heilmann S, Kiesslich R, von Rahden BH, Allescher HD, Schulz HG, Wijmenga C, Heneka MT, Lang H, Hopfner KP, Nöthen MM, Boeckxstaens GE, de Bakker PI, Knapp M, Schumacher J. Nat. Genet. 46 901-904 (2014)
  2. 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)
  3. 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)
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  12. Coupling between side chain interactions and binding pocket flexibility in HLA-B*44:02 molecules investigated by molecular dynamics simulations. Ostermeir K, Springer S, Zacharias M. Mol. Immunol. 63 312-319 (2015)
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  14. 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)
  15. 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)
  16. pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity. Jiang W, Strohman MJ, Somasundaram S, Ayyangar S, Hou T, Wang N, Mellins ED. Sci Rep 5 17333 (2015)
  17. 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)
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  19. Type 1 diabetes associated HLA-DQ2 and DQ8 molecules are relatively resistant to HLA-DM mediated release of invariant chain-derived CLIP peptides. Zhou Z, Reyes-Vargas E, Escobar H, Rudd B, Rockwood AL, Delgado JC, He X, Jensen PE. Eur. J. Immunol. 46 834-845 (2016)
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  21. An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. Parra-López CA, Bernal-Estévez D, Yin L, Vargas LE, Pulido-Calixto C, Salazar LM, Calvo-Calle JM, Stern LJ. PLoS ONE 9 e100639 (2014)
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