scholarly journals Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

1991 ◽  
Vol 174 (2) ◽  
pp. 371-379 ◽  
Author(s):  
S K Sanders ◽  
R O Fox ◽  
P Kavathas
Keyword(s):  
Amino Acids ◽  
Tertiary Structure ◽  
Mutational Analysis ◽  
Hla Class I ◽  
Antibody Binding ◽  
Variable Domain ◽  
Class I ◽  
Adhesion Assay ◽  
A Cell ◽  
Species Specific

The T cell co-receptor, CD8, binds to the alpha 3 domain of HLA class I (Salter, R.D., R.J. Benjamin, P.K. Wesley, S.E. Buxton, T.P.J. Garrett, C. Clayberger, A.M. Krensky, A.M. Norman, D.R. Littman, and P. Parham. 1990. Nature [Lond.]. 345:41; Connolly, J.M., T.A. Potter, E.M. Wormstall, and T.H. Hansen. 1988. J. Exp. Med. 168:325; and Potter, T.A., T.V. Rajan, R.F. Dick II, and J.A. Bluestone. 1989. Nature [Lond.]. 337:73). To identify regions of CD8 that are important for binding to HLA class I, we performed a mutational analysis of the CD8 molecule in the immunoglobulin (Ig)-like variable domain. Our mutational analysis was based on our finding that using a cell-cell adhesion assay murine CD8 (Lyt-2) did not bind to human class I. Since the interaction of human CD8 with HLA class I is species specific, we substituted nonconservative amino acids from mouse CD8 and analyzed the ability of the mutated CD8 molecules expressed in COS 7 cells to bind HLA class I-bearing B lymphoblastoid cells, UC. Mutants with the greatest effect on binding were located in a portion of the molecule homologous to the first and second hypervariable regions of an antibody combining site. In addition, a panel of 12 anti-CD8 monoclonal antibodies were used to stain the 10 CD8 mutants, and amino acids that affected antibody binding were localized on the crystal structure of the Bence-Jones homodimer, REI. Support for an Ig-like structure of CD8 can be found in the pattern of substitutions affecting antibody binding. This work supports the similar tertiary structure of the CD8 alpha-terminal domain and an Ig variable domain.

scholarly journals Interaction between CD8 and major histocompatibility complex (MHC) class I mediated by multiple contact surfaces that include the alpha 2 and alpha 3 domains of MHC class I.

1995 ◽  
Vol 182 (5) ◽  
pp. 1275-1280 ◽  
Author(s):  
J Sun ◽  
D J Leahy ◽  
P B Kavathas
Keyword(s):  
Mhc Class I ◽  
Cytotoxic T Lymphocytes ◽  
Mutational Analysis ◽  
Surface Glycoprotein ◽  
Class I ◽  
Adhesion Assay ◽  
Cell Surface Glycoprotein ◽  
Histocompatibility Complex ◽  
A Cell ◽  
Beta 2 Microglobulin

The cell surface glycoprotein CD8 functions as a coreceptor with the TCR on cytotoxic T lymphocytes. Mutational analysis of the binding site of CD8 for MHC class I predicted that distinct surfaces of CD8 would interact with both the alpha 2 and alpha 3 domains of class I. Using a cell-cell adhesion assay, we identified three residues Q115, D122, and E128 in the alpha 2 domain of class I critical for interaction with CD8. The side chains of these residues point towards a cavity formed by the alpha 1/alpha 2 platform, the alpha 3 domain and beta 2-microglobulin (beta 2m) of class I. These residues were predicted to contact CD8 based on a bivalent model of interaction between one CD8 alpha/alpha homodimer and two MHC class I molecules. These results therefore provide support for the model.

scholarly journals Dimorphism of HLA-E and its Disease Association

2019 ◽  
Vol 20 (21) ◽  
pp. 5496 ◽  
Author(s):  
Leonid Kanevskiy ◽  
Sofya Erokhina ◽  
Polina Kobyzeva ◽  
Maria Streltsova ◽  
Alexander Sapozhnikov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Tertiary Structure ◽  
Hla Class I ◽  
Surface Expression ◽  
Class I ◽  
Human Populations ◽  
Cytotoxic Lymphocytes ◽  
Main Function ◽  
Mhc I ◽  
High Level

HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.

scholarly journals Mutational Analysis of RsbT, an Activator of the Bacillus subtilis Stress Response Transcription Factor, σB

2004 ◽  
Vol 186 (9) ◽  
pp. 2789-2797 ◽  
Author(s):  
Robyn L. Woodbury ◽  
Tingqiu Luo ◽  
Lindsay Grant ◽  
W. G. Haldenwang
Keyword(s):  
Amino Acids ◽  
Bacillus Subtilis ◽  
Tertiary Structure ◽  
Mutational Analysis ◽  
Physical Stress ◽  
Negative Regulator ◽  
Alanine Scanning Mutagenesis ◽  
Charged Amino Acids ◽  
Carboxy Terminal ◽  
Stress Pathway

ABSTRACT σB, the stress-activated σ factor of Bacillus subtilis, requires the RsbT protein as an essential positive regulator of its physical stress pathway. Stress triggers RsbT to both inactivate the principal negative regulator of the physical stress pathway (RsbS) by phosphorylation and activate a phosphatase (RsbU) required for σB induction. Neither the regions of RsbT that are involved in responding to stress signaling nor those required for downstream events have been established. We used alanine scanning mutagenesis to examine the contributions of RsbT's charged amino acids to the protein's stability and activities. Eleven of eighteen rsbT mutations blocked σB induction by stress. The carboxy terminus of RsbT proved to be particularly important for accumulation in Bacillus subtilis. Four of the five most carboxy-terminal mutations yielded rsbT alleles whose products were undetectable in B. subtilis extracts. Charged amino acids in the central region of RsbT were less critical, with four of the five substitutions in this region having no measurable effect on RsbT accumulation or activity. Only when the substitutions extended into a region of kinase homology was σB induction affected. Six other RsbT variants, although present at levels adequate for activity, failed to activate σB and displayed significant changes in their ability to interact with RsbT's normal binding partners in a yeast dihybrid assay. These changes either dramatically altered the proteins' tertiary structure without affecting their stability or defined regions of RsbT that are involved in multiple interactions.

scholarly journals Mutational Analysis of the HLA Class II Interaction with Epstein-Barr Virus Glycoprotein 42

2003 ◽  
Vol 77 (13) ◽  
pp. 7655-7662 ◽  
Author(s):  
Marisa P. McShane ◽  
Maureen M. Mullen ◽  
Keith M. Haan ◽  
Theodore S. Jardetzky ◽  
Richard Longnecker
Keyword(s):  
Epstein Barr Virus ◽  
Mutational Analysis ◽  
Hla Class I ◽  
Class Ii ◽  
Hla Class Ii ◽  
Class I ◽  
Viral Glycoprotein ◽  
Barr Virus ◽  
Lectin Family ◽  
Epstein Barr

ABSTRACT Entry of Epstein-Barr virus (EBV) into B lymphocytes requires the binding of viral glycoprotein 42 (gp42), a C-type lectin family member, to HLA class II. Recently, the structure of the gp42:HLA-DR1 complex was determined. In order to confirm the interaction as determined in the structural study and to identify other potential interactive residues, a mutational analysis of HLA class II was performed. A secreted form of gp42 (sgp42) reacted with a conformation-specific monoclonal antibody and blocked EBV infection. The binding of sgp42 and EBV entry to two sets of HLA class II mutants were tested. The first set of mutants were based on the known interaction of the C-type lectin Ly49A with HLA class I, and the second set of mutants were based on the identified interface in the gp42:HLA-DR1 complex. As expected, none of the mutants that would be predicted to interfere with the interaction of Ly49A with class I affected the interaction of gp42 with HLA class II, whereas mutants in amino acids identified in the gp42:HLA-DR1 structure inhibited sg42 binding to class II. In general, sgp42 binding correlated with efficient entry of EBV, as demonstrated by the necessity of glutamic acid 46 or arginine 72 in class II molecules. Furthermore, other HLA class II residues buried within the interface of gp42 and HLA class II when mutated had either no effect or a decrease in both binding and entry and implicate a region of class II important in stabilizing the interaction with gp42. These studies provide insight into the entry and fusion processes of the critical interaction between gp42 and HLA class II.

scholarly journals Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 480 ◽  
Author(s):  
Jerzy K. Kulski
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Endogenous Retrovirus ◽  
Class I ◽  
Specific Gene ◽  
Regulation Of Transcription ◽  
Antisense Sequence ◽  
Species Specific

The HCP5 RNA gene (NCBI ID: 10866) is located centromeric of the HLA-B gene and between the MICA and MICB genes within the major histocompatibility complex (MHC) class I region. It is a human species-specific gene that codes for a long noncoding RNA (lncRNA), composed mostly of an ancient ancestral endogenous antisense 3′ long terminal repeat (LTR, and part of the internal pol antisense sequence of endogenous retrovirus (ERV) type 16 linked to a human leukocyte antigen (HLA) class I promoter and leader sequence at the 5′-end. Since its discovery in 1993, many disease association and gene expression studies have shown that HCP5 is a regulatory lncRNA involved in adaptive and innate immune responses and associated with the promotion of some autoimmune diseases and cancers. The gene sequence acts as a genomic anchor point for binding transcription factors, enhancers, and chromatin remodeling enzymes in the regulation of transcription and chromatin folding. The HCP5 antisense retroviral transcript also interacts with regulatory microRNA and immune and cellular checkpoints in cancers suggesting its potential as a drug target for novel antitumor therapeutics.

scholarly journals HLA Class I–sensitized Renal Transplant Patients Have Antibody Binding to SLA Class I Epitopes

2019 ◽  
Vol 103 (8) ◽  
pp. 1620-1629 ◽  
Author(s):  
Gregory R. Martens ◽  
Joseph M. Ladowski ◽  
Jose Estrada ◽  
Zheng-Yu Wang ◽  
Luz M. Reyes ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Hla Class I ◽  
Antibody Binding ◽  
Class I ◽  
Transplant Patients ◽  
Renal Transplant Patients

scholarly journals In vivo, RFX5 binds differently to the human leucocyte antigen-E, -F, and -G gene promoters and participates in HLA class I protein expression in a cell type-dependent manner

Immunology ◽  
2004 ◽  
Vol 111 (1) ◽  
pp. 53-65 ◽  
Author(s):  
Philippe Rousseau ◽  
Krzysztof Masternak ◽  
Michal Krawczyk ◽  
Walter Reith ◽  
Jean Dausset ◽  
...  
Keyword(s):  
Protein Expression ◽  
Human Leucocyte Antigen ◽  
Hla Class I ◽  
Class I ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Cell Type ◽  
A Cell

The peptide length specificity of some HLA class I alleles is very broad and includes peptides of up to 25 amino acids in length

2009 ◽  
Vol 46 (8-9) ◽  
pp. 1911-1917 ◽  
Author(s):  
Melissa J. Bell ◽  
Jacqueline M. Burrows ◽  
Rebekah Brennan ◽  
John J. Miles ◽  
Judy Tellam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hla Class I ◽  
Class I ◽  
Peptide Length

scholarly journals Identification of a  -Cell-Specific HLA Class I Restricted Epitope in Type 1 Diabetes

Diabetes ◽  
2003 ◽  
Vol 52 (11) ◽  
pp. 2647-2651 ◽  
Author(s):  
C. Panagiotopoulos ◽  
H. Qin ◽  
R. Tan ◽  
C. B. Verchere
Keyword(s):  
Type 1 Diabetes ◽  
Hla Class I ◽  
Class I ◽  
A Cell ◽  
Restricted Epitope

scholarly journals Cytotoxic T lymphocytes from HLA-A2 transgenic mice specific for HLA-A2 expressed on human cells.

1988 ◽  
Vol 168 (3) ◽  
pp. 1157-1162 ◽  
Author(s):  
E J Bernhard ◽  
A X Le ◽  
J A Barbosa ◽  
E Lacy ◽  
V H Engelhard
Keyword(s):  
Transgenic Mice ◽  
Cytotoxic T Lymphocytes ◽  
Human Cell ◽  
Hla Class I ◽  
Human Cells ◽  
Class I ◽  
Class I Mhc ◽  
Endogenous Proteins ◽  
Species Specific ◽  
Hla A2.1

CTL clones were derived from HLA-A2.1 transgenic mice by immunization with a human cell expressing HLA-A2.1. None of these clones lysed murine transfectants, and only 3 of 23 lysed monkey transfectants expressing HLA-A2. In contrast, all of these clones lysed a wide variety of human cells expressing HLA-A2.1. These results demonstrate the existence of species-specific epitopes on the HLA-A2.1 molecule, and suggest that these epitopes are formed by the association of class I MHC products with one or more endogenous species-specific molecules. These results provide an explanation for the frequently observed failure of HLA class I-specific CTL to recognize these antigens on murine transfectants. These results also suggest that such endogenous proteins may also contribute to the formation of epitopes recognized by allospecific CTL.

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