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 47

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

J. H. Brown, T S Jardetzky, J C Gorga … (1993)

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.

L J Stern, J. Brown, T Jardetzky … (1994)

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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Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size.

Dario A. A. Vignali, J Strominger, Kimberly R. Urban … (1992)

Peptides bound to class I molecules are 8-10 amino acids long, and possess a binding motif representative of peptides that bind to a given class I allele. In the only published study of naturally processed peptides bound to class II molecules (mouse I-Ab and I-Eb), these peptides were longer (13-17 amino acids) and had heterogenous carboxy terminals but precise amino-terminal truncations. Here we report the characterization of acid-eluted peptides bound to HLA-DR1 by high-performance liquid chromatography, mass spectrometry and microsequencing analyses. The relative molecular masses of the peptides varied between 1,602 and 2,996 (13-25 residues), the most abundant individual M(r) values being between 1,700 and 1,800, corresponding to an average peptide length of 15 residues. Complete sequence data were obtained for twenty peptides derived from five epitopes, of which all but one were from self proteins. These peptides represented sets nested at both the N- and C-terminal ends. Binding experiments confirmed that all of the isolated peptides had high affinity for the groove of DR1. Alignment of the peptides bound to HLA-DR1 and the sequences of 35 known HLA-DR1-binding peptides revealed a putative motif. Although peptides bound to class II molecules may have some related features (due to the nonpolymorphic HLA-DR alpha-chain), accounting for degenerate binding to different alleles, particular amino acids in the HLA-DR beta-chains presumably define allelic specificity of peptide binding.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 21 December 2010

Publication date (Electronic): 5 December 2010

Publication date (Print): January 2011

Publication date PMC-release: 1 July 2011

Volume: 12

Issue: 1

Pages: 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

Correspondence: kai_wucherpfennig@ 123456dfci.harvard.edu

[*]

Current address: Pfizer, Cambridge, MA 02140

Article

Manuscript ID: nihpa251598

DOI: 10.1038/ni.1967

PMC ID: 3018327

PubMed ID: 21131964

SO-VID: 42e52f06-d377-4aae-9c79-e67cdcf33a43

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