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      HLA-DM Captures Partially Empty HLA-DR Molecules for Catalyzed Peptide Removal

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          Abstract

          The mechanisms of HLA-DM catalyzed peptide exchange remain uncertain. We found that all stages of the interaction of DM with HLA-DR were dependent on the occupancy state of the peptide binding groove. High-affinity peptides were protected from removal by DM through two mechanisms: peptide binding induced dissociation of a long-lived complex of empty DR and DM, and high-affinity DR-peptide complexes bound DM only very slowly. Non-binding covalent DR-peptide complexes were converted to efficient DM binders upon truncation of an N-terminal peptide segment that emptied the P1 pocket and disrupted conserved hydrogen bonds to MHC. DM thus only binds to DR conformers in which a critical part of the binding site is vacant, due to spontaneous peptide motion.

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          Most cited references 49

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          Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1.

          The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II alpha beta heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
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            Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide.

            An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
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              Mediation by HLA-DM of dissociation of peptides from HLA-DR.

              Human leukocyte antigen (HLA)-DM is an unconventional major histocompatibility complex (MHC) class II heterodimer that is important for B-cell-mediated antigen processing and presentation to MHC class II-restricted T cells. HLA-DM is encoded by two genes, DMA and DMB, which map to the MHC class II region, and shares some homology with MHC class I and class II proteins. Here we define the biochemical role of HLA-DM. Recombinant soluble HLA-DM heterodimers have been purified from culture supernatants of insect cell transformants. At pH 5.0, they induce the dissociation of a subset of peptides bound to HLA-DR, including a nested set of class-II-associated invariant chain peptides (CLIP). This process liberates HLA-DR and leads to the enhanced binding of exogenous peptides.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature immunology
                1529-2908
                1529-2916
                21 December 2010
                5 December 2010
                January 2011
                1 July 2011
                : 12
                : 1
                : 54-61
                Affiliations
                [1 ] Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115
                [2 ] Program in Immunology, Harvard Medical School, Boston, MA 02115
                [3 ] Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, 14195 Berlin, Germany
                [4 ] Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA 02139
                [5 ] Boston Biomedical Research Institute, Watertown, MA 02472
                Author notes
                [*]

                Current address: Pfizer, Cambridge, MA 02140

                Article
                nihpa251598
                10.1038/ni.1967
                3018327
                21131964

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 NS044914-08 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 NS044914-07 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 NS044914-06 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 NS044914-05A1 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 NS044914-04 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057493-05 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057493-04 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057493-03 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057493-02 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057493-01 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-13 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-12 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-11 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-10S1 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-10 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-09 ||AI
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI045757-08 ||AI
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                Immunology

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