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PubMed2006

A modular concept of HLA for comprehensive peptide binding prediction.

A variety of algorithms have been successful in predicting human leukocyte antigen (HLA)-peptide binding for HLA variants for which plentiful experimental binding data exist. Although predicting binding for only the most common HLA variants may provide sufficient population coverage for vaccine design, successful prediction for as many HLA variants as possible is necessary to understand the immune response in transplantation and immunotherapy. However, the high cost of obtaining peptide binding data limits the acquisition of binding data. Therefore, a prediction algorithm, which applies the binding information from well-studied HLA variants to HLA variants, for which no peptide data exist, is necessary. To this end, a modular concept of class I HLA-peptide binding prediction was developed. Accurate predictions were made for several alleles without using experimental peptide binding data specific to those alleles. We include a comparison of module-based prediction and supertype-based prediction. The modular concept increased the number of predictable alleles from 15 to 75 of HLA-A and 12 to 36 of HLA-B proteins. Under the modular concept, binding data of certain HLA alleles can make prediction possible for numerous additional alleles. We report here a ranking of HLA alleles, which have been identified to be the most informative. Modular peptide binding prediction is freely available to researchers on the web at http://www.peptidecheck.org .

Alleles↗

PubMed2004

Analysis and prediction of affinity of TAP binding peptides using cascade SVM.

The generation of cytotoxic T lymphocyte (CTL) epitopes from an antigenic sequence involves number of intracellular processes, including production of peptide fragments by proteasome and transport of peptides to endoplasmic reticulum through transporter associated with antigen processing (TAP). In this study, 409 peptides that bind to human TAP transporter with varying affinity were analyzed to explore the selectivity and specificity of TAP transporter. The abundance of each amino acid from P1 to P9 positions in high-, intermediate-, and low-affinity TAP binders were examined. The rules for predicting TAP binding regions in an antigenic sequence were derived from the above analysis. The quantitative matrix was generated on the basis of contribution of each position and residue in binding affinity. The correlation of r = 0.65 was obtained between experimentally determined and predicted binding affinity by using a quantitative matrix. Further a support vector machine (SVM)-based method has been developed to model the TAP binding affinity of peptides. The correlation (r = 0.80) was obtained between the predicted and experimental measured values by using sequence-based SVM. The reliability of prediction was further improved by cascade SVM that uses features of amino acids along with sequence. An extremely good correlation (r = 0.88) was obtained between measured and predicted values, when the cascade SVM-based method was evaluated through jackknife testing. A Web service, TAPPred (http://www.imtech.res.in/raghava/tappred/ or http://bioinformatics.uams.edu/mirror/tappred/), has been developed based on this approach.

ATP-Binding Cassette Transporters↗

PubMed1996

The peptide binding motif of the disease associated HLA-DQ (alpha 1* 0501, beta 1* 0201) molecule.

To identify the binding motifs of peptides which bind to the celiac disease and insulin-dependent-diabetes-mellitus (IDDM)-associated DQ2 molecule, peptides were eluted from affinity-purified DQ2 molecules. The eluted peptides were separated by reverse-phase HPLC. Prominent peptide peaks and the remaining pool of peptides were sequenced by Edman degradation. Truncated variants of eight different peptides with a length of 9-19 amino acids were identified; among them class II-associated invariant chain peptides (CLIP) and peptides that stem from HLA class I alpha, HLA-DQ alpha 1*0501, Ig and CD20 molecules. Data from the pool sequencing and the biochemical binding analyses of synthetic variants of an eluted high-affinity ligand (HLA class I alpha 46-60), indicate that the side chains of amino acid residues at relative position P1 (bulky hydrophobic), P4 (negatively charged or aliphatic), P6 (Pro or negatively charged), P7 (negatively charged) and P9 (bulky hydrophobic) are important for binding of peptides to DQ2. Computer modeling of the DQ2 with variants of the high-affinity ligand in the groove suggests that peptides bind to DQ2 through the primary anchors P1, P7 and P9 and making additional advantageous interactions using the P4 and P6 positions.

Alleles↗

PubMed1993

Promiscuous and allele-specific anchors in HLA-DR-binding peptides.

The major histocompatibility complex (MHC) class II molecules are highly polymorphic membrane glycoproteins that bind peptide fragments of proteins and display them for recognition by CD4+ T cells. To understand the effect of human MHC class II polymorphism on peptide-MHC interaction, we have isolated M13 phage from a large M13 peptide display library by selection with DRB1*0401 and DRB1*1101 molecules, as recently described for DRB1*0101. Sequence analysis of the peptide-encoding region of DR-bound phage led to the identification of position-specific anchor residues, defining motifs for peptide binding to DR molecules. The three DR motifs share two anchor residues at relative positions 1 and 4, while allele-specific anchor residues have been identified at position 6. These results provide a biophysical basis for both the promiscuity and the specificity of peptide recognition by DR molecules.

Alleles↗

PubMed2004

Selective targeting of a laccase from Stachybotrys chartarum covalently linked to a carotenoid-binding peptide.

Atwo-step targeting strategy was used to identify improved laccases for bleaching carotenoid-containing stains on fabric. We first applied a modified phage display technique to identify peptide sequences capable of binding specifically to carotenoid stains and not to fabric. Prior deselection on the support on which the carotenoid was localized, increased stringency during the biopanning target selection process, and analysis of the phage peptides' binding to the target after acid elution and polymerase chain reaction (PCR) postacid elution, were used to isolate phage peptide libraries with increased binding selectivity and affinity. Peptide sequences were selected based on identified consensus motifs. We verified the enhanced carotenoid-binding properties of the peptide YGYLPSR and subsequently cloned and expressed C-terminal variants of laccase from Stachybotrys chartarum containing carotenoid-binding peptides YGYLPSR, IERSAPATAPPP, KASAPAL, CKASAPALC, and SLLNATK. These targeted peptide-laccase fusions demonstrate enhanced catalytic properties on stained fabrics.

Carotenoids↗

PubMed1995

The gp120 envelope of HIV-1 binds peptides in a similar manner to human leukocyte antigens.

OBJECTIVE: All the conserved regions of HIV gp120 have at least some partial homology with human leukocyte antigen (HLA) class I or class II. One functional similarity is the ability of gp120 and HLA class II to bind CD4. Given the close association between HIV-induced disease and the amount of immune activation and anergy, features closely associated with chronic allogenic stimulation, we asked whether gp120 shared any other properties of HLA, in this case the ability to bind peptides. DESIGN: T-cell epitope peptides known to bind to soluble HLA class I or class II were photolabelled and made radioactive. Cross-linking of modified peptides to soluble HLA class I, II and gp120 was activated by ultraviolet light and analysed by sodium dodecylsulphate-polyacrylamide gel electrophoresis. RESULTS: A signal peptide binding to HLA class I and a haemagglutinin peptide that binds to HLA class II were found to bind soluble gp120 specifically; binding and cross-linking could be competed out with excess of the unmodified peptides but not unrelated control peptides. Molecular modelling of gp120 suggests shared anchor sites for peptides binding to both HLA and gp120 soluble molecules. CONCLUSIONS: The ability to bind these two peptides suggests that gp120 has a peptide-binding site of broad specificity, which if functional in vivo, could compete with normal peptide loading of major histocompatibility complex (MHC) class I and/or class II peptides, as well as aberrantly stimulate the T-cell receptor (by virtue of its potential to be mistaken for an allogenic MHC/peptide complex), resulting in immune activation, anergy and apoptosis in susceptible hosts.

Amino Acid Sequence↗

PubMed1991

Functional mapping of MHC class II polymorphic residues. The alpha-chain controls the specificity for binding an Ad-versus an A k-restricted peptide and the beta-chain region 65-67 controls T cell recognition but not peptide binding.

MHC proteins are polymorphic cell surface glycoproteins involved in the binding of peptide Ag and their presentation to T lymphocytes. The polymorphic amino acids of MHC proteins are primarily located in the N-terminal domains and are thought to influence T cell recognition both by influencing the binding of peptide Ag and by direct contact with the T cell receptor. In order to determine the relative importance of individual polymorphic amino acids in Ag presentation, a number of groups have taken the approach of interchanging polymorphic amino acids between different alleles of MHC protein in an attempt to define which of the polymorphisms influence peptide binding and which influence T cell recognition by direct contact with the TCR. The peptide OVA323-339 has been previously shown to bind to the MHC class II protein Ad and to have a much lower affinity for Ak, whereas the peptide hen egg lysozyme 46-61 binds well to Ak and poorly to Ad. In the present report, we have analyzed the ability of purified wild-type MHC class II proteins as well as the ability of three different hybrid molecules between Ad and Ak to bind and present these peptides. We find that the alpha-chain of the MHC class II protein plays a critical role in the binding of HEL46-61 and confers the specificity for binding OVA323-339, regardless of which beta-chain is present. We also find that the beta-chain region 65-67 does not control the specificity of peptide binding to the MHC protein, but is important in T cell responses to preformed MHC-peptide complexes, suggesting a role for this region in contacting the TCR.

Amino Acid Sequence↗

PubMed2002

A von Willebrand factor-derived heparin-binding peptide regulates cell--substrate adhesive strength and chemokinesis behavior.

The ability of a soluble heparin-binding oligopeptide sequence derived from the von Willebrand factor (vWF) to modulate the adhesion and chemokinetic migration behavior of arterial smooth muscle cells was assessed using a novel glass microsphere centrifugation assay and automated time-lapse fluorescence videomicroscopy, respectively. Treatment of cells grown on fibronectin-coated substrates with the heparin-binding peptide resulted in the disassembly of focal adhesions, as assessed by immunohistochemical staining. These observations were consistent with six-fold decrease in cell--substrate adhesive strength (P<0.001), a biphasic effect on migration speed (P<0.05), as well as a dose-dependent reduction in the percentage of motile cells and the cell dispersion coefficient (mu=S(2)T/2). The specificity of this response to the vWF-derived heparin-binding peptide was supported by the absence of an observed effect in the presence of either a scrambled peptide or a consensus heparin-binding peptide sequence of similar heparin affinity. These data support the notion that competitive interactions between cell surface heparan sulfates with heparin-binding peptide domains located in soluble peptide fragments may modulate chemokinetic cell migration behavior and other adhesion-related processes.

Animals↗

PubMed1991

Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules.

HLA-DR molecules are heterodimeric transmembrane glycoproteins that associate intracellularly with a polypeptide known as the invariant (I) chain. Shortly before expression of the HLA-DR alpha beta dimer on the cell surface, however, the I chain is removed from the intracellular alpha beta I complex by a mechanism thought to involve proteolysis. In this report, we show that treatment of purified alpha beta I with the cysteine proteinase cathepsin B results in the specific proteolysis of the HLA-DR-associated I chain in vitro. As a consequence of this, the I chain is removed and free alpha beta dimers are released from alpha beta I. Although alpha beta I fails to bind an immunogenic peptide, the released alpha beta dimers acquire the ability to bind the peptide after proteolysis of the I chain. These results suggest that the I chain inhibits immunogenic peptide binding to alpha beta I early during intracellular transport and demonstrate that proteolysis is likely to be the in vivo mechanism of I chain removal.

Antigen-Presenting Cells↗

PubMed1990

Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding.

Class II major histocompatibility complex (MHC) molecules are heterodimeric cell surface glycoproteins which bind and present immunogenic peptides to T lymphocytes. Such peptides are normally derived from protein antigens internalized and proteolytically degraded by the antigen-presenting cell. Class I MHC molecules also bind immunogenic peptides, but these are derived from proteins synthesized within the target cell. Whereas class I molecules seem to bind peptides in the endoplasmic reticulum, class II molecules are thought to bind peptides late in transport. Intracellular class II molecules associate in the endoplasmic reticulum with a third glycoprotein, the invariant (I) chain, which is proteolytically removed before cell surface expression of the alpha beta class II heterodimer. It has been suggested that the I chain prevents peptides from associating with class II molecules early in transport. Preventing such binding until the class II molecules enter an endosomal compartment could maintain the functional dichotomy between class I and class II MHC molecules. We have examined the ability of I chain-associated HLA-DR5 molecules to bind a well characterized influenza haemagglutinin-derived peptide (HAp). The results show that whereas mature HLA-DR alpha beta dimers effectively bind this peptide, the I chain-associated form does not.

B-Lymphocytes↗

PubMed2003

Interaction of neuropeptide Y and Hsp90 through a novel peptide binding region.

Hsp90 is a molecular chaperone that binds and assists refolding of non-native and/or labile polypeptides and also bind various peptides. However, the rules of how Hsp90 recognizes substrates have not been well characterized. By surface plasmon resonance measurements, a physiologically active peptide, neuropeptide Y (NPY), with a strong binding property to Hsp90 was identified from screening of 38 randomly selected peptide candidates. We showed that the carboxy-terminal fragment of NPY (NPY13-36), which forms an amphipathic alpha-helix structure, preserved the strong binding to Hsp90. Immunoprecipitation and immunoblotting using HeLa cell extracts revealed that newly synthesized NPY precursors bound to Hsp90, suggesting that the in vitro binding experiments identified an interactive peptide in vivo. Proteolytic cleavage of the NPY13-36/Hsp90 complex, as well as binding site analysis using deletion mutants of Hsp90, revealed the NPY binding locus on Hsp90alpha as the 192 amino acid region following the N-terminal domain. By electron microscopic analysis using an anti-Hsp90 antibody against the sequence proximal to the highly charged region, we showed that the Hsp90 dimer bound to NPY13-36 at both ends. Mutation of arginine residues in NPY13-36 to alanine abrogated binding to Hsp90. Our studies indicate that the hinge region after the N-terminal domain of Hsp90 and the positive charges on NPY are important for this interaction.

Amino Acid Sequence↗

PubMed2006

Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules.

The chimpanzee (Pan troglodytes) is an important model for studying the immune response to several human pathogens, but the study of correlates of immunity has been hindered by the fact that little is known about the epitope-binding specificity of chimpanzee (Patr) class I MHC. In the present study we have characterized the peptide binding specificity of several common Patr class I molecules. Using single amino acid substitution analogs and large peptide libraries, quantitative peptide binding motifs have been derived for Patr A*0101, A*0701, A*0901, B*0101, and B*2401. Each molecule was found to bind peptides using position 2 and the C terminus as main anchor contacts. On the other hand, each Patr molecule is associated with a unique binding specificity, and the range of specificities is similar to that seen amongst HLA alleles. A high degree of cross-reactivity was noted between Patr A*0701 and Patr A*0901, suggesting the existence of a Patr-specific supertype. Consistent with previous studies suggesting that some cross-reactivity may exist between HLA and Patr alleles, Patr A*0901 was found to have an appreciable degree of cross-reactivity with molecules of the HLA A24-supertype. Finally, utilizing motif scans and peptide binding and intracellular cytokine staining assays, 77 hepatitis B virus (HBV)-derived epitopes were identified in five chimpanzees that were recently convalescent from acute HBV infection. Because the Patr alleles studied herein were found to be very common in two different chimpanzee populations, the present data should facilitate the use of chimpanzees for immunological studies.

Amino Acid Motifs↗

PubMed1999

A conformational change in the human major histocompatibility complex protein HLA-DR1 induced by peptide binding.

To investigate a conformational change accompanying peptide binding to class II MHC proteins, we probed the structure of a soluble version of the human class II MHC protein HLA-DR1 in empty and peptide-loaded forms. Peptide binding induced a large decrease in the effective radius of the protein as determined by gel filtration, dynamic light scattering, and analytical ultracentrifugation. It caused a substantial increase in the cooperativity of thermal denaturation and induced alterations in MHC polypeptide backbone structure as determined by circular dichroism. These changes suggest a condensation of the protein around the bound peptide. An antibody specific for beta58-69 preferentially bound the empty protein, indicating that the peptide-induced conformational change involves the beta-subunit helical region. The conformational change may have important implications for the mechanisms of intracellular antigen presentation pathways.

Amino Acid Sequence↗

PubMed2000

Radio-labeled receptor-binding peptides: a new class of radiopharmaceuticals.

Radio-labeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals. In vertebrates, these peptides transmit their biological function by binding to their specific receptor on the target cell surface. This specific receptor-binding property is exploited when the radio-labeled peptide is used as a radiopharmaceutical. The high-binding affinity for its receptor facilitates retention of the peptide in receptor-expressing tissues, whereas its relatively small size facilitates rapid clearance from the blood and other nontarget tissues. Receptor-binding peptides labeled with gamma-emitters can be used to visualize receptor-positive cells in vivo. In addition, when labeled with beta- or alpha-emitters, these peptides can be used for peptide-receptor radionuclide therapy. Various receptors are overexpressed on particular tumor types, and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Furthermore, peptides binding receptors on granulocytes can be used to image infectious and inflammatory foci, whereas peptides binding receptors on activated thrombocytes can be used for thrombus imaging. Here, the peptide analogs that are under development for these applications are reviewed.

Animals↗

PubMed2003

Functional analysis of HLA-DP polymorphism: a crucial role for DPbeta residues 9, 11, 35, 55, 56, 69 and 84-87 in T cell allorecognition and peptide binding.

The information available on the specific function of HLA-DP and the structure-function relationships is very limited. Here, single amino acid substitutions of HLA-DPB1*02012 have been used to analyze the role of polymorphic residues of the DPbeta1 domain on DP-mediated T cell allorecognition and peptide binding. Using a panel of specific anti-HLA-DP mAb, we identified the HLA-DP residues involved in the recognition by these mAb, with a crucial role for DPbeta56 for most of the mAb assayed. Individual substitutions at residues 9, 11, 35, 55, 56 and 69 completely abrogated T cell recognition mediated by two different HLA-DPw2-allospecific T cell clones (8.3 and 8.9). Interestingly single changes at positions 9, 11, 35 and 55 of HLA-DPbeta also altered the binding of peptides AAII(12-27) and IIP(53-65), natural ligands of the HLA-DPB1*02012 molecule. Individual changes at residues located in pocket 1 (84, 85, 86 and 87 from HLA-DPbeta) led to a partial reduction in cytotoxic T lymphocyte-mediated lysis and also partially affected peptide binding. However, the simultaneous substitution of these positions completely abolished both T cell allorecognition and peptide binding, suggesting a major role for polymorphisms at pocket 1 in HLA-DP function. Molecular modeling, used to predict changes induced by amino acid substitutions, supported the functional data. Taken together, these results strongly suggest that polymorphic residues 84, 85, 86 and 87 at pocket 1, residues 9, 35 and 55 at pocket 9, and residues 11 and 69 at pockets 6 and 4 respectively play a key role in HLA-DP function, probably by modifying the way the peptide is bound within the groove of HLA-DP2 and determining changes in the conformation of the MHC-peptide complex recognized by the TCR.

Antibodies, Monoclonal↗

PubMed2006

Materials specificity and directed assembly of a gold-binding peptide.

Adsorption studies of a genetically engineered gold-binding peptide, GBP1, were carried out using a quartz-crystal microbalance (QCM) to quantify its molecular affinity to noble metals. The peptide showed higher adsorption onto and lower desorption from a gold surface compared to a platinum substrate. The material specificity, that is, the preferential adsorption, of GBP1 was also demonstrated using gold and platinum micropatterned on a silicon wafer containing native oxide. The biotinylated three-repeat units of GBP1 were preferentially adsorbed onto gold regions delineated using streptavidin-conjugated quantum dots (SAQDs). These experiments not only demonstrate that an inorganic-binding peptide could preferentially adsorb onto a metal (Au) rather than an oxide (SiO2) but also onto one noble metal (Au) over another (Pt). This result shows the utility of an engineered peptide as a molecular erector in the directed immobilization of a nanoscale hybrid entity (SAQDs) over selected regions (Au) on a fairly complex substrate (Au and Pt micropatterned regions on silica). The selective and controlled adsorption of inorganic-binding peptides may have significant implications in nano- and nanobiotechnology, where they could be genetically tailored for specific use in the development of self-assembled molecular systems.

Adsorption↗

PubMed1996

Specificity and degeneracy in peptide binding to HLA-B7-like class I molecules.

The HLA-B7-like binding supertype includes several different HLA-B molecules. Herein, the primary and secondary anchor specificities of the five most common HLA-B7-like molecules (B*0702, B*3501, B51, B*5301, and B*5401) were defined by the use of molecular binding assays, analogue peptides, and large sets of peptides corresponding to naturally occurring sequences. All five B7-like molecules analyzed preferentially bound 9-mers, with a stringent requirement for proline in position 2, while a variety of hydrophobic or aromatic residues were well tolerated at the C-terminal anchor position. Although most peptides bound in an allele-specific fashion, approximately 20% of the binders identified were degenerate and bound at least three of the five B7-like molecules analyzed with affinities of 500 nM or less. It was also noted that, in general, peptides that bind with high affinity to any given one B7-like molecule were also most frequently capable of degenerate binding. Prominent roles for secondary anchors in positions 1 and 3 were observed for most B7-like molecules, and secondary anchor motifs were utilized to derive an HLA-B7-like supermotif. The validity of this B7-like supermotif was tested by a blind prediction set. Finally, the B7-like supermotif was utilized to derive a general strategy for rationally engineering peptide analogues of naturally occurring sequences with greatly increased binding affinity and degeneracy. Such engineered supermotif binding peptides may be of significant utility in the development of peptide-based vaccines against chronic viral diseases and cancer.

Alleles↗

PubMed1996

Characterization of the peptide-binding specificity of HLA-B*7301.

Previous studies showed the human MHC class I heavy chain HLA-B*7301 has a sequence very divergent from other class I alleles. Despite the unusual sequence, we predicted B*7301 would retain the peptide-binding function typical of other HLA-A, B and C glycoproteins, and sequence similarity to B*2705 in a region of the peptide-binding site known as the B pocket suggested B*7301 would bind peptides with Arg at position 2. To test this hypothesis, the peptide-binding specificity of B*7301 was investigated. Sequence analysis of peptides bound endogenously by B*7301 indeed found selectivity for nonamer peptides possessing Arg at position 2 and a preference for small nonpolar residues such as Pro or Ala at the C terminus was also revealed. B*7301 therefore possesses the potential to function as a conventional antigen presenting class I glycoprotein. Functional similarities between B*7301 and B*2705 are discussed in the context of the association of B*27 subtypes with susceptibility to ankylosing sponylitis and arthritic diseases.

Binding Sites↗