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Binding of viral antigens to major histocompatibility complex class i h-2d(b) molecules is controlled by dominant negative elements at peptide non-anchor residues - implications for peptide selection and presentation

Academic Article
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Overview

authors

  • Hudrisier, D.
  • Mazarguil, H.
  • Laval, F.
  • Oldstone, Michael
  • Gairin, J. E.

publication date

  • July 1996

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Binding of viral antigens to major histocompatibility complex (MHC) class I molecules is a critical step in the activation process of CD8(+) cytotoxic T lymphocytes. In this study, we investigated the impact of structural factors at non-anchor residues in peptide-MHC interaction using the model of lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse. Altering viral genes by making reassortants, recombinants, and using synthetic peptides, CD8(+) cytotoxic T lymphocytes were shown to recognize only three H-2Db-restricted epitopes, GP amino acids 33-41/43, GP 276-286, and NP 396-404. However, LCMV NP and GP proteins contain 31 other peptides bearing the H-2Db motif. These 34 LCMV peptides and 11 other known H2-Db-restricted peptides were synthesized and examined for MHC binding properties. Despite the presence of the H-2Db binding motif, the majority of LCMV peptides showed weak or no affinity for H-2Db. We observed that dominant negative structural elements located at non-anchor positions played a crucial role in peptide-MHC interaction. By comparative sequence analysis of strong versus non-binders and using molecular modeling, we delineated these negative elements and evaluated their impact on peptide-MHC interaction. Our findings were validated by showing that a single mutation of a favorable non-anchor residue in the sequence of known viral epitopes for a negative element resulted in dramatic reduction of antigen presentation properties, while conversely, substitution of one negative for a positive element in the sequence of a non-binder conferred to the peptide an ability to now bind to MHC molecules.

subject areas

  • Amino Acid Sequence
  • Animals
  • Antigens, Viral
  • Computer Simulation
  • Cytotoxicity, Immunologic
  • H-2 Antigens
  • Histocompatibility Antigen H-2D
  • Lymphocytic choriomeningitis virus
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Oligopeptides
  • Protein Binding
  • Structure-Activity Relationship
  • T-Lymphocytes, Cytotoxic
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

PubMed ID

  • 8663374
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Additional Document Info

start page

  • 17829

end page

  • 17836

volume

  • 271

issue

  • 30

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