Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HLA-B27 is a human major histocompatibility complex class I product defined by its antigenic specificity with conventional alloantisera. Detailed studies using monoclonal antibodies, cytotoxic T lymphocytes (CTL), and isoelectric focusing (IEF) gel electrophoresis demonstrated the heterogeneity in the B27 antigen. We have previously identified a unique variant molecule of B27 designated locally as B27d which is distinguished from other B27 variants by isoelectric point, serologic reactivity, and by a cloned CTL recognition. A gene encoding the B27d variant has been cloned and a complete nucleotide sequence has been determined. Compared to the sequence of the prototype B27a, the B27d has a single base substitution at codon 59 (B27a:TAT--B27d: CAT) in exon 2 responsible for Tyr to His substitution. A His residue at this position in the alpha 1 domain is unique among the known class I sequences and this single amino acid change is apparently sufficient to alter the epitope(s) recognized by antibody and cytotoxic T cell receptor. Previous primary structural analysis of the other five B27 variants has revealed differences of two to four amino acids. The combined structural data on the B27 variants indicate that (1) HLA-B27 represents a family of closely related B locus alleles that share the B27 allospecificity and differ by a limited number (one to four) of amino acid substitutions and (2) point mutation as well as gene conversion might be the mechanism responsible for the allelic variation of B27 antigen family.
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PMID:Molecular analysis of the variant alloantigen HLA-B27d (HLA-B*2703) identifies a unique single amino acid substitution. 328 82

Cytotoxic T lymphocytes (CTLs) are the most powerful weapon of the immune system to eliminate cells infected by intracellular parasites or tumors. However, very often, escape mechanisms overcome CTL immune surveillance by impairing the classical HLA class I antigen-processing pathway. Here, we describe a strategy for CTL activation based on the ability of Tat to mediate transcellular delivery of viral proteins encompassing HLA class I-restricted epitopes. In this system, the recombinant protein TAT-NpFlu containing the transduction domain of Tat of human immunodeficiency virus type 1 fused to the amino acid region 301 to 498 of the nucleoprotein of influenza A virus is proven to sensitize different human cells to lysis by HLA-B27-restricted, Flu 383-391-specific CTL lines. The fusion protein is processed very effectively, since a comparable biological effect is obtained with an amount of protein between 1 and 2 orders of magnitude lower than that of the synthetic peptide. Interestingly, while part of TAT-NpFlu undergoes fast and productive cleavage, a large amount of it remains intact for up to 24 h. Confocal microscopy shows that TAT-NpFlu accumulates in the trans-Golgi network (TGN), where it starts to be detectable 1 h after transduction. Using TAT-NpFlu mutants and hybrid constructs, we demonstrate that enrichment in the TGN occurs only when the carboxy-terminal region of NpFlu (amino acids 400 to 498) is present. These data disclose an unconventional route for presentation of epitopes restricted for HLA class I molecules.
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PMID:The C terminus of the nucleoprotein of influenza A virus delivers antigens transduced by Tat to the trans-golgi network and promotes an efficient presentation through HLA class I. 1630 24

Nascent HLA-class I molecules are stabilized by proteasome-derived peptides in the ER and the new complexes proceed to the cell surface through the post-ER vesicles. It has been shown, however, that less stable complexes can exchange peptides in the Trans Golgi Network (TGN). HLA-B27 are the most studied HLA-class I molecules due to their association with Ankylosing Spondylitis (AS). Chimeric proteins driven by TAT of HIV have been exploited by us to deliver viral epitopes, whose cross-presentation by the HLA-B27 molecules was proteasome and TAP-independent and not restricted to Antigen-Presenting Cells (APC). Here, using these chimeric proteins as epitope suppliers, we compared with each other and with the HLA-A2 molecules, the two HLA-B*2705 and B*2709 alleles differing at residue 116 (D116H) and differentially associated with AS. We found that the antigen presentation by the two HLA-B27 molecules was proteasome-, TAP-, and APC-independent whereas the presentation by the HLA-A2 molecules required proteasome, TAP and professional APC. Assuming that such difference could be due to the unpaired, highly reactive Cys-67 distinguishing the HLA-B27 molecules, C67S mutants in HLA-B*2705 and B*2709 and V67C mutant in HLA-A*0201 were also analyzed. The results showed that this mutation did not influence the HLA-A2-restricted antigen presentation while it drastically affected the HLA-B27-restricted presentation with, however, remarkable differences between B*2705 and B*2709. The data, together with the occurrence on the cell surface of unfolded molecules in the case of C67S-B*2705 mutant but not in that of C67S-B*2709 mutant, indicates that Cys-67 has a more critical role in stabilizing the B*2705 rather than the B*2709 complexes.
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PMID:Characterization of a proteasome and TAP-independent presentation of intracellular epitopes by HLA-B27 molecules. 2280 46