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

2004 ◽  
Vol 200 (11) ◽  
pp. 1445-1454 ◽  
Author(s):  
Michael J. Miley ◽  
Ilhem Messaoudi ◽  
Beatrix M. Metzner ◽  
Yudong Wu ◽  
Janko Nikolich-Žugich ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class I ◽  
Structural Basis ◽  
Anchor Residue ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Simplex Virus

Major histocompatibility complex (MHC) class I variants H-2Kb and H-2Kbm8 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 B498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against Kb–HSV8 cannot recognize H-2Kbm8–HSV8. However, substitution of SerP2 to GluP2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2Kbm8–H2E was recognized whereas H-2Kb–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.

scholarly journals The strength of selection is consistent across both domains of the MHC class I peptide-binding groove in birds

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Piotr Minias ◽  
Ke He ◽  
Peter O. Dunn
Keyword(s):  
Mhc Class I ◽  
Peptide Binding ◽  
Variable Region ◽  
Molecular Data ◽  
Class I ◽  
Amino Acid Polymorphism ◽  
Exon 2 ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Avian Mhc

Abstract Background The Major Histocompatibility Complex (MHC) codes for the key vertebrate immune receptors responsible for pathogen recognition. Foreign antigens are recognized via their compatibility to hyper-variable region of the peptide-binding groove (PBR), which consists of two separate protein domains. Specifically, the PBR of the MHC class I receptors, which recognize intra-cellular pathogens, has two α domains encoded by exon 2 (α1) and exon 3 (α2) of the same gene. Most research on avian MHC class I polymorphism has traditionally focused exclusively on exon 3 and comparisons of selection between the two domains have been hampered by the scarcity of molecular data for exon 2. Thus, it is not clear whether the two domains vary in their specificity towards different antigens and whether they are subject to different selective pressure. Results Here, we took advantage of rapidly accumulating genomic resources to test for the differences in selection patterns between both MHC class I domains of the peptide-binding groove in birds. For this purpose, we compiled a dataset of MHC class I exon 2 and 3 sequences for 120 avian species from 46 families. Our phylogenetically-robust approach provided strong evidence for highly consistent levels of selection on the α1 and α2 domains. There were strong correlations in all selection measures (number of positively/negatively selected residues and dN/dS ratios) between both PBR exons. Similar positive associations were found for the level of amino acid polymorphism across the two domains. Conclusions We conclude that the strength of selection and the level of polymorphism are highly consistent between both peptide-binding domains (α1 and α2) of the avian MHC class I.

scholarly journals Mapping the peptide binding groove of MHC class I

2021 ◽  
Author(s):  
Janine-Denise Kopicki ◽  
Ankur Saikia ◽  
Stephan Niebling ◽  
Christian G&uumlnther ◽  
Maria M. Garcia-Alai ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Mhc Class I ◽  
Peptide Binding ◽  
Essential Element ◽  
Native Mass Spectrometry ◽  
Class I ◽  
Peptide Antigens ◽  
Novel Approach ◽  
Peptide Binding Groove ◽  
Binding Groove

An essential element of adaptive immunity is the selective binding of peptide antigens by major histocompatibility complex (MHC) class I proteins and their presentation to cytotoxic T lymphocytes on the cell surface. Using native mass spectrometry, we here analyze the binding of peptides to an empty disulfide-stabilized HLA-A*02:01 molecule. This novel approach allows us to examine the binding properties of diverse peptides. The unique stability of our MHC class I even enables us to determine the binding affinity of complexes, which are suboptimally loaded with truncated or charge-reduced peptides. Notably, a unique erucamide adduct decouples affinity analysis from peptide identity alleviating issues usually attributed to clustering. We discovered that two anchor positions at the binding surface between MHC and peptide can be stabilized independently and further analyze the contribution of other peptidic amino acids on the binding. We propose this as an alternative, likely universally applicable method to artificial prediction tools to estimate the binding strength of peptides to MHC class I complexes quickly and efficiently. This newly described MHC class I-peptide binding affinity quantitation represents a much needed orthogonal, confirmatory approach to existing computational affinity predictions and has the potential to eliminate binding affinity biases and thus accelerate drug discovery in infectious diseases autoimmunity, vaccine design, and cancer immunotherapy.

scholarly journals The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

2001 ◽  
Vol 166 (7) ◽  
pp. 4422-4428 ◽  
Author(s):  
Naoki Matsumoto ◽  
Wayne M. Yokoyama ◽  
Somei Kojima ◽  
Kazuo Yamamoto
Keyword(s):  
Mhc Class I ◽  
Nk Cell ◽  
Peptide Binding ◽  
Class I ◽  
Peptide Binding Groove ◽  
Binding Groove

scholarly journals T cell receptor (TCR) recognition of MHC class I variants: intermolecular second-site reversion provides evidence for peptide/MHC conformational variation.

1996 ◽  
Vol 184 (1) ◽  
pp. 253-258 ◽  
Author(s):  
R Dyall ◽  
D H Fremont ◽  
S C Jameson ◽  
J Nikolić-Zugić
Keyword(s):  
Hydrogen Bond ◽  
T Cell ◽  
Mhc Class I ◽  
T Cell Receptor ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class I ◽  
Hydrogen Bond Network ◽  
Binding Studies ◽  
Bond Network

We investigated mechanistic differences in antigen presentation between murine MHC class I variants H-2K(b) and H-2K(bm)8. H-2K(bm)8 differs from H-2K(b) by four residues at the floor of the peptide-binding site, affecting its B pocket which interacts with the second (P2) residue of the peptide. The rest of the molecule, including the T cell receptor (TCR)-contacting residues, is identical to H-2K(b). Due to this variation, CTLs that recognize the ovalbumin 257-264 and HSV gB 498-505 peptides on H-2K(b) cannot recognize them on H-2K(bm)8. This could be due to impaired peptide binding or an altered peptide: K(bm)8 conformation. Peptide binding studies ruled out the first explanation. Molecular modeling indicated that the most obvious consequence of amino acid variation between peptide/H-2K(b) and peptide/H-2K(bm)8 complexes would be a loss of the conserved hydrogen bond network in the B pocket of the latter. This could cause conformational variation of bound peptides. Intermolecular second-site reversion was used to test this hypothesis: P2-substituted OVA and HSV peptides, engineered to restore the hydrogen bond network of the B pocket, were the only ones which restored CTL recognition. These results provide a molecular understanding of peptide/MHC conformational variation.

scholarly journals Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA*0101 and DRB1*0401)

2002 ◽  
Vol 195 (5) ◽  
pp. 571-581 ◽  
Author(s):  
Jens Hennecke ◽  
Don C. Wiley
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class Ii ◽  
Histocompatibility Complex ◽  
Peptide Binding Groove ◽  
Binding Groove

The α/β T cell receptor (TCR) HA1.7 specific for the hemagglutinin (HA) antigen peptide from influenza A virus is HLA-DR1 restricted but cross-reactive for the HA peptide presented by the allo-major histocompatibility complex (MHC) class II molecule HLA-DR4. We report here the structure of the HA1.7/DR4/HA complex, determined by X-ray crystallography at a resolution of 2.4 Å. The overall structure of this complex is very similar to the previously reported structure of the HA1.7/DR1/HA complex. Amino acid sequence differences between DR1 and DR4, which are located deep in the peptide binding groove and out of reach for direct contact by the TCR, are able to indirectly influence the antigenicity of the pMHC surface by changing the conformation of HA peptide residues at position P5 and P6. Although TCR HA1.7 is cross-reactive for HA presented by DR1 and DR4 and tolerates these conformational differences, other HA-specific TCRs are sensitive to these changes. We also find a dependence of the width of the MHC class II peptide-binding groove on the sequence of the bound peptide by comparing the HA1.7/DR4/HA complex with the structure of DR4 presenting a collagen peptide. This structural study of TCR cross-reactivity emphasizes how MHC sequence differences can affect TCR binding indirectly by moving peptide atoms.

Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove

1999 ◽  
Vol 49 (6) ◽  
pp. 532-540 ◽  
Author(s):  
B. Yassine-Diab ◽  
P. Carmichael ◽  
Fatima-Ezzahra L'Faqihi ◽  
Giovanna Lombardi ◽  
Sarah Deacock ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Allelic Variation ◽  
Peptide Binding ◽  
Cell Receptor ◽  
Class Ii ◽  
Receptor Usage ◽  
Peptide Binding Groove ◽  
Binding Groove

scholarly journals ERp57 interacts with conserved cysteine residues in the MHC class I peptide-binding groove

FEBS Letters ◽  
2007 ◽  
Vol 581 (10) ◽  
pp. 1988-1992 ◽  
Author(s):  
Antony N. Antoniou ◽  
Susana G. Santos ◽  
Elaine C. Campbell ◽  
Sarah Lynch ◽  
Fernando A. Arosa ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Peptide Binding ◽  
Class I ◽  
Cysteine Residues ◽  
Peptide Binding Groove ◽  
Binding Groove
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