A prominent natural H-2 Kd ligand is derived from protein tyrosine kinase JAK1

Harpur, Ailsa G.; Ziemiecki, Andrew; Wilks, Andrew F.; Falk, Kirsten; Rötzschke, Olaf; Rammensee, H. G.

doi:10.1016/0165-2478(93)90188-8

Cited by 15 publications

(9 citation statements)

References 10 publications

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“…Degradation of the JAK1 21-mer Peptide-The JAK1 21-mer peptide is part of JAK1 tyrosine kinase and contains the MHC class I ligand SYFPEITHI (28). Incubation of this peptide with mammalian proteasomes leads to efficient generation of the MHC I ligand (10,25), which is flanked by two dominant cleavage sites after Phe 7 and Ile 16 , respectively.…”

Section: And ␤5/pre2mentioning

confidence: 99%

Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants

Dick

Nussbaum

Deeg³

et al. 1998

Journal of Biological Chemistry

256

173

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Proteasomes generate peptides that can be presented by major histocompatibility complex (MHC) class I molecules in vertebrate cells. Using yeast 20 S proteasomes carrying different inactivated ␤-subunits, we investigated the specificities and contributions of the different ␤-subunits to the degradation of polypeptide substrates containing MHC class I ligands and addressed the question of additional proteolytically active sites apart from the active ␤-subunits. We found a clear correlation between the contribution of the different subunits to the cleavage of fluorogenic and long peptide substrates, with ␤5/Pre2 cleaving after hydrophobic, ␤2/Pup1 after basic, and ␤1/Pre3 after acidic residues, but with the exception that ␤2/Pup1 and ␤1/Pre3 can also cleave after some hydrophobic residues. All proteolytic activities including the "branched chain amino acid-preferring" component are associated with ␤5/Pre2, ␤1/Pre3, or ␤2/ Pup1, arguing against additional proteolytic sites. Because of the high homology between yeast and mammalian 20 S proteasomes in sequence and subunit topology and the conservation of cleavage specificity between mammalian and yeast proteasomes, our results can be expected to also describe most of the proteolytic activity of mammalian 20 S proteasomes leading to the generation of MHC class I ligands.

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Section: And ␤5/pre2mentioning

confidence: 99%

Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants

Dick

Nussbaum

Deeg³

et al. 1998

Journal of Biological Chemistry

256

173

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“…The sequences of a number of naturally processed peptides that are presented by K d have been identified, including self-peptides (12,(15)(16)(17)(18)(19)(20)(21)60) and those encoded by viruses (14,22,23), parasites (24,25), and bacteria (26). The first virally encoded T-cell epitope ever described was in fact a K d -binding peptide derived from influenza A/PR/8/34 nucleoprotein (27).…”

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confidence: 99%

Structural Definition of the H-2Kd Peptide-binding Motif

Mitaksov

Fremont

2006

Journal of Biological Chemistry

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Classic major histocompatibility complex (MHC) proteins associate with antigen-and self-derived peptides in an allele-specific manner. Herein we present the crystal structure of the MHC class I protein H-2K d (K d ) expressed by BALB/c mice in complex with an antigenic peptide derived from influenza A/PR/8/34 nucleoprotein (Flu, residues 147-155, TYQRTRALV). Analysis of our structure in conjunction with the sequences of naturally processed epitopes provides a comprehensive understanding of the dominant K d peptide-binding motif. We find that Flu residues Tyr P2 , Thr P5 , and Val P9 are sequestered into the B, C, and F pockets of the K d groove, respectively. The shape and chemistry of the polymorphic B pocket make it an optimal binding site for the side chain of Tyr P2 as the dominant anchoring residue of nonameric peptides. The non-polar F pocket limits the amino acid repertoire at P9 to hydrophobic residues such as Ile, Leu, or Val, whereas the C pocket restricts the size of the P5-anchoring side chain. We also show that Flu is accommodated in the complex through an unfavorable kink in the otherwise extended peptide backbone due to the presence of a prominent ridge in the K d groove. Surprisingly, this backbone conformation is strikingly similar to D b -presented peptides despite the fact that these proteins employ distinct motif-anchoring strategies. The results presented in this study provide a solid foundation for the understanding of K d -restricted antigen presentation and recognition events.Class I major histocompatibility complex (MHC) 2 proteins serve a critical role in the adaptive immune response by binding short peptide fragments intracellularly and presenting them at the cell surface for surveillance by cytotoxic T lymphocytes (1-4). Structural studies of human and murine MHC class I proteins in complex with a variety of peptides have revealed conservative structural elements that promote efficient binding and presentation of peptide epitopes (5-9). Peptides of 8 -10 residues are bound in a predominantly extended conformation within a narrow groove formed by two antiparallel ␣-helices positioned above an eight-strand ␤-sheet platform. Conservative hydrogen bonding networks are established in the binding groove with peptide mainchain and terminal atoms that enable largely sequence-independent ligation.Although low affinity, kinetically short-lived peptide-MHC complexes can be established by highly diverse epitope sequences, stable association requires the anchoring of peptide side chains into specific pockets in the MHC groove. MHC polymorphisms are clustered in these pockets (3, 10, 11), and their shape and chemistry impose constraints that are reflected by allele-specific motifs found in the sequences of naturally processed peptides (12, 13). For example, H-2 d cell lines (P815) and H-2 b cell lines (EL4) infected with the same influenza virus present different antigenic peptides for CTL recognition (14). Thus, outbred populations that express varied MHC proteins can survey diverse peptide fragme...

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“…In prophylactic models, vaccination is performed before tumor challenge, whereas in the therapeutic model, tumor inoculation precedes vaccination. In the murine mastocytoma cell line P815, an unusually large proportion of approximately 5% of the MHC class I molecules in the H-2K d haplotype present the single peptide SYFPEITHI (14,15). This peptide displayed prominently on cancer cells is derived from murine tyrosine kinase JAK-1.…”

Section: Resultsmentioning

confidence: 99%

“…This peptide displayed prominently on cancer cells is derived from murine tyrosine kinase JAK-1. We chose this prominent ''self''-epitope, (14,15) to test the peptide vaccine approach in the P815 tumor model. Unaltered self-antigens may be recognized by the immune system as TAs if inappropriately expressed, as was recently shown for tyrosinase (50).…”

Section: Resultsmentioning

confidence: 99%

Cell-free tumor antigen peptide-based cancer vaccines

Schmidt

Buschle

Zauner

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The central role that tumor antigen-derived peptides play in induction of antitumor immunity makes them ideal candidates for peptide-based cancer vaccines. We have demonstrated that ''transloading'' is an efficient strategy for importing short peptide ligands into antigen-presenting cells in vitro. Postulating that the transloading procedure might effect peptide uptake by antigen-presenting cells in vivo as well, we tested this approach for the generation of peptidebased cancer vaccines. In the P815 mastocytoma system, we vaccinated mice by s.c. injection of a single, known natural peptide derived from JAK-1 kinase. Whereas vaccination with peptide alone or mixed with incomplete Freund's adjuvant was ineffective, application of the peptide in conjunction with the polycation poly-L-lysine protected a significant number of animals against tumor challenge. Dependent upon the type of poly-L-lysine applied, protection against tumor take was comparable to that achieved with irradiated whole-cell vaccines, genetically modified to secrete granulocyte-macrophage colony-stimulating factor. In the murine melanoma M-3, a combination of four putative tumor antigen-derived peptides was tested as a cancer vaccine. Administered in combination with polycations, these peptides evoked potent antitumor immunity that could not be obtained with the peptides alone or peptides emulsified in incomplete Freund's adjuvant. However, peptide-polycation vaccines applied to the M-3 model were not as efficient as cellular control vaccines, consisting of irradiated interleukin 2 or granulocyte-macrophage colonystimulating factor-secreting tumor cells.

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A prominent natural H-2 Kd ligand is derived from protein tyrosine kinase JAK1

Cited by 15 publications

References 10 publications

Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants

Contribution of Proteasomal β-Subunits to the Cleavage of Peptide Substrates Analyzed with Yeast Mutants

Structural Definition of the H-2Kd Peptide-binding Motif

Cell-free tumor antigen peptide-based cancer vaccines

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