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Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution

Major histocompatibility complex (MHC) class I variants H-2K(b) and H-2K(bm8) differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulat...

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Autores principales: Miley, Michael J., Messaoudi, Ilhem, Metzner, Beatrix M., Wu, Yudong, Nikolich-Žugich, Janko, Fremont, Daved H.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211956/
https://www.ncbi.nlm.nih.gov/pubmed/15557346
http://dx.doi.org/10.1084/jem.20040217
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author Miley, Michael J.
Messaoudi, Ilhem
Metzner, Beatrix M.
Wu, Yudong
Nikolich-Žugich, Janko
Fremont, Daved H.
author_facet Miley, Michael J.
Messaoudi, Ilhem
Metzner, Beatrix M.
Wu, Yudong
Nikolich-Žugich, Janko
Fremont, Daved H.
author_sort Miley, Michael J.
collection PubMed
description Major histocompatibility complex (MHC) class I variants H-2K(b) and H-2K(bm8) differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B(498-505) epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against K(b)–HSV8 cannot recognize H-2K(bm8)–HSV8. However, substitution of Ser(P2) to Glu(P2) (peptide H2E) reversed T cell receptor (TCR) recognition; H-2K(bm8)–H2E was recognized whereas H-2K(b)–H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.
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spelling pubmed-22119562008-03-11 Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution Miley, Michael J. Messaoudi, Ilhem Metzner, Beatrix M. Wu, Yudong Nikolich-Žugich, Janko Fremont, Daved H. J Exp Med Article Major histocompatibility complex (MHC) class I variants H-2K(b) and H-2K(bm8) differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B(498-505) epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against K(b)–HSV8 cannot recognize H-2K(bm8)–HSV8. However, substitution of Ser(P2) to Glu(P2) (peptide H2E) reversed T cell receptor (TCR) recognition; H-2K(bm8)–H2E was recognized whereas H-2K(b)–H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface. The Rockefeller University Press 2004-12-06 /pmc/articles/PMC2211956/ /pubmed/15557346 http://dx.doi.org/10.1084/jem.20040217 Text en Copyright © 2004, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Miley, Michael J.
Messaoudi, Ilhem
Metzner, Beatrix M.
Wu, Yudong
Nikolich-Žugich, Janko
Fremont, Daved H.
Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title_full Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title_fullStr Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title_full_unstemmed Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title_short Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
title_sort structural basis for the restoration of tcr recognition of an mhc allelic variant by peptide secondary anchor substitution
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211956/
https://www.ncbi.nlm.nih.gov/pubmed/15557346
http://dx.doi.org/10.1084/jem.20040217
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