Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs

Rudensky, Alexander Y.; Preston-Hurlburt, Paula; al-Ramadi, Basel K.; Rothbard, Jonathan B.; Janeway, Charles A.

doi:10.1038/359429a0

Cited by 220 publications

(127 citation statements)

References 26 publications

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“…This difference is reflected in a strong clustering of positively charged residues in cycles 12-14 in the pool sequencing analysis of E k and E d eluted peptides (Tables 1 and 3). Weak signals for aliphatic residues are found as well, whereas P9 is clearly dominated by Arg and P chain polymorphic residues predicted ligand specificity H-2E 3 P chain polymorphic residues predicted ligand specificity Lys. A similar preference of basic amino acids at the P9 anchor of isolated ligands is observed for the HLA-DRB5*0101 molecule, where the corresponding pocket has a negative character (29).…”

Section: Discussionmentioning

confidence: 86%

“…However, such motifs are less apparent with ligands eluted from class II MHC molecules because these peptides vary extensively in their length, complicating the alignment of isolated natural ligands (2)(3)(4)(5)(6). Therefore, most of the information of class II binding specificity is derived from peptide binding studies using mutations of known T cells epitopes (7)(8)(9)(10)(11) or by in vitro selection of peptides derived from phage libraries (12).…”

Section: Introductionmentioning

confidence: 99%

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Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Schild

Grüneberg

Pougialis³

et al. 1995

Int Immunol

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Motifs of peptides naturally associated with H-2E k and E d molecules were determined by (I) pool sequencing of natural ligand mixtures and (II) sequencing of Individual natural ligands followed by their alignment to the basic motif suggested by pool sequencing. The data reveal nine amlno acid motifs with Interaction sites at relative positions P1, P4, P6 and P9, with specificities that are identical at some but different at other anchor positions between E d and E k motifs, Illustrating the different requirements for peptides to be presented by these two MHC molecules. The anchors with the most restricted specificity are P1 and P9.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Schild

Grüneberg

Pougialis³

et al. 1995

Int Immunol

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“…There are many studies of peptides bound to IA b (39,40,47,48). However, these studies alone have not yet yielded a consensus on the peptide binding motif for IA b .…”

Section: Resultsmentioning

confidence: 99%

“…For example, p3K is derived from pE␣, which also has four Ala residues in the same positions. pE␣ binds well to both IA b and IA d (40,41). A peptide of ovalbumin, VHAAHAEINEAG, is presented by either IA b or IA d to the T cell hybridoma 43).…”

Section: Resultsmentioning

confidence: 99%

Alternate interactions define the binding of peptides to the MHC molecule IA^b

Liu

Dai

Crawford

et al. 2002

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

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T he crystal structures of a variety of MHCI (1-9) and MHCII (10-23) molecules have revealed their features that lead to stable peptide binding. Conserved amino acids of MHCI interact with the N terminus and C terminus of the peptide in virtually all isotypes and alleles. Between these termini, the peptide can vary in length and in the path it takes through the binding groove, often bulging out of the groove in the middle. In MHCII, the N and C termini of the peptide generally extend beyond the binding groove and do not interact with the MHCII molecule. Rather, H-bonding interactions between the peptide backbone and conserved amino acids of the MHCII ␣-helices force the peptide to take a similar, extended path through the groove of all MHCII isotypes and alleles.The unique interactions that determine the allelic specificity of peptide binding seem to be controlled by the character of pockets within the interior of the binding groove that preferentially accept particular amino acid side chains. Because the MHC amino acids that line these pockets are among the most genetically variable, their depth, shape, and chemistry vary considerably among MHC alleles and isotypes, and they appear to be the most important factor in the specificity of peptide binding.In the current study we have solved the crystal structure of the mouse MHCII molecule IA b with a bound immunogenic peptide variant of a dominant peptide derived from the MHCII E␣ protein that is found in IA b in some strains of mice (24). Despite the high stability and immunogenicity of this complex, the four usual p1, p4, p6, and p9 peptide side chain binding pockets of IA b are largely unfilled, because alanines occur in the peptide at these positions. Rather, the stability of this peptide͞MHCII complex can be attributed to the combination of the conserved interactions with the peptide backbone as well as extensive unique interactions of the IA b molecule with other peptide amino acids particularly at the N-terminal end and the p7 position of the peptide. These results suggest that IA b can achieve stable peptide binding in more than one way and may account for the previous difficulty in defining the IA b peptidebinding motif. Materials and MethodsPreparation of Soluble IA b . The production of soluble IA b containing a peptide attached to the ␤-chain N terminus via a flexible peptide linker has been described (25). In the original constructions, peptides included both the E␣-derived peptide, ASFEAQGALANIAVDKA (pE␣), which occupies about 10% of natural IA b , and an immunogenic variant, ASFEAQKAK-ANKAVDKA (p3K), in which three positions in the peptide (underlined) had lysines substituted for the E␣ peptide amino acids. For crystallization, the construct was altered to use a shortened form of p3K, FEAKGAKANKAVD, and to shorten the IA b ␣ and ␤ chains to the predicted ends of the ␣2 and ␤2 domains. The construct was cloned into a previously described dual promoter baculovirus transfer vector (26, 27) and introduced into BacVector 3000 version of AcNPV baculovirus ...

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“…33 For both MHC class I and class II peptides, allele-specific epitope forecasts have been devised because of the existence of motifs for the amino acid residues involved in the binding of the peptide to the MHC molecule. 36,39,40 Targeting antigen to the class I and class II pathways Specific sequences exist that can target different subcellular organelles. The addition of an ER signal sequence to the 5′ end of a peptide can bypass the TAP pathway and target the peptide for co-translational insertion into the ER.…”

Section: Antigen Processing: Where Cell Mediated Immune Responses Beginmentioning

confidence: 99%

The next wave of recombinant and synthetic anticancer vaccines

Irvine

Restifo

1995

Seminars in Cancer Biology

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The identification of tumor-associated antigens (TAA) recognized by T lymphocytes makes the development of antigen-specific synthetic and recombinant vaccines possible. The expression of TAA within a recombinant vector increases control over the kinetics and quantity, the molecular form, and the subcellular location of the immunogen delivered. The next generation of antitumor vaccines employs cytokines and costimulatory molecules expressed in concert with TAA that are capable of augmenting the activation and proliferation of antitumor immune responses. The ultimate goal of these new strategies, the treatment of established cancer, is now being realized in animal models.Keywords tumor-associated antigen; recombinant vaccines; immunotherapy; recombinant fowlpox; recombinant adenovirus Elements of the cellular immune system clearly play a role in antitumor immunity. 1-4 The recent cloning of new TAA recognized by T lymphocytes allows for the development of recombinant and synthetic anticancer vaccines. Combining new techniques in molecular biology, virology and synthetic protein chemistry, specific vaccines can be developed that increase the control the immunotherapist has over the quantity and kinetics of TAA expression, the intracellular compartment into which the TAA are expressed and what cell types or tissues are used to express TAA in vivo. In addition to the classic concept of viral vaccination in which individuals are immunized against antigens prior to natural challenge with the pathogen, therapeutic cancer vaccination may also be used to induce or enhance antitumor immune reactions in patients who already have cancer. This review will discuss examples of current recombinant and synthetic vaccine strategies designed to enhance or elicit antitumor responses.

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Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs

Cited by 220 publications

References 26 publications

Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Alternate interactions define the binding of peptides to the MHC molecule IA^b

The next wave of recombinant and synthetic anticancer vaccines

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Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs

Cited by 220 publications

References 26 publications

Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Natural ligand motifs of H-2E molecules are allele specific and illustrate homology to HLA-DR molecules

Alternate interactions define the binding of peptides to the MHC molecule IAb

The next wave of recombinant and synthetic anticancer vaccines

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About

Alternate interactions define the binding of peptides to the MHC molecule IA^b