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At least 721 records · Page 40Linked to original sources
PubMed1993

Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop.

Incretins are intestinal factors that stimulate postprandial insulin secretion in preparation for subsequent rises in plasma levels of ingested nutrients. Glucose-dependent insulinotropic peptide (GIP), a duodenal endocrine peptide, is ideally located for such a function. In contrast, the intestinal proglucagon-derived peptide (PGDP), truncated GLP-1 [GLP-1(7-37) or tGLP-1] is equipotent to GIP in insulinotropic activity, but due to its localization in the distal ileum, appears to be poorly situated to fulfill an incretin role in response to direct nutrient stimulation. Despite its distribution, rapid increments in plasma levels of tGLP-1 have been noted in response to nutrient ingestion. We have recently reported that GIP (but not other nutrient-stimulated duodenal endocrine peptides) can stimulate intestinal PGDP secretion in vitro, and therefore hypothesized that GIP might regulate secretion of the intestinal PGDPs, including tGLP-1, in response to nutrient ingestion in vivo in the rat. Placement of either fat or glucose directly into the ileal lumen was demonstrated to significantly stimulate secretion of the intestinal PGDPs (P < 0.05), whereas fat or glucose in the duodenal lumen significantly increased plasma levels of GIP (P < 0.05). In addition, however, duodenal fat treatment also increased the secretion of intestinal PGDPs into the circulation (P < 0.05), with levels rising to same extent as observed after direct administration of fat into the ileum. The rise in plasma GIP levels in response to duodenal fat treatment occurred slightly before the increments in intestinal PGDP levels, suggesting a relationship between the two peptides. Intravenous infusion of GIP to give concentrations similar to those observed after duodenal fat administration induced a 2-fold increase in plasma levels of intestinal PGDPs that was independent of glycemic levels (P < 0.05). No increment in intestinal PGDPs was found in response to infusion of another duodenal endocrine peptide, cholecystokinin. Thus, these data demonstrate a specific effect of GIP to stimulate secretion of the intestinal PGDPs in vivo in the rat. This enteroendocrine loop between the duodenal peptide GIP and the ileal PGDPs may account for some of the early rises in secretion of tGLP-1 observed in response to nutrient ingestion.

Animals↗
PubMed1988

Molecular forms of katacalcin, calcitonin gene-related peptide and gastrin-releasing peptide, in a human medullary thyroid carcinoma.

Peptides synthesized by a human medullary thyroid carcinoma were purified to homogeneity by reverse-phase high performance liquid chromatography and structurally characterized by determination of amino acid composition, amino acid sequence, and fast atom bombardment mass spectra. The katacalcin-related material in the tumor extract was heterogeneous. Katacalcin (1-21) represented the predominant molecular form but metabolites, identified as katacalcin (1-20), (1-19), (1-15) and (1-13), were also identified in high concentration. Calcitonin gene-related peptide-I was isolated from the tumor but calcitonin gene-related peptide-II was absent. A minor component of calcitonin gene-related peptide-like immunoreactivity was of higher molecular weight and may represent an incompletely processed form of the prohormone. Gastrin-releasing peptide (1-27) and gastrin-releasing peptide (18-27) (neuromedin C) were isolated from the tumor but gastrin-releasing peptide (14-27) and bombesin were absent.

Adult↗
PubMed1998

Local control of peptide conformation: stabilization of cis proline peptide bonds by aromatic proline interactions.

In the native state of proteins there is a marked tendency for an aromatic amino acid to precede a cis proline. There are also significant differences between the three aromatic amino acids with Tyr exhibiting a noticeably higher propensity than Phe or Trp to precede a cis proline residue. In order to study the role that local interactions play in these conformation preferences, a set of tetrapeptides of the general sequence acetyl-Gly-X-Pro-Gly-carboxamide (GXPG), where X = Tyr, Phe, Trp, Ala, or cyclohexyl alanine, were synthesized and studied by nmr. Analysis of the nmr data shows that none of the peptides adopt a specific backbone structure. Ring current shifts, the equilibrium constant, the Van't Hoff enthalpy, and the measured rate of cis-trans isomerization all indicate that the cis proline conformer is stabilized by favorable interactions between the aromatic ring and the proline residue. Analysis of the side chain conformation of the aromatic residue and analysis of the chemical shifts of the pyrrolidine ring protons shows that the aromatic side chain adopts a preferred conformation in the cis form. The distribution of rotamers and the effect of an aromatic residue on the cis-trans equilibrium indicate that the preferred conformation is populated to approximately 62% for the Phe containing peptide, 67% for the Tyr containing peptide, and between 75 and 80% for the Trp containing peptide. The interaction is unaffected by the addition of 8M urea. These local interactions favor an aromatic residue immediately preceding a cis proline, but they cannot explain the relative propensities for Phe-Pro, Tyr-Pro, and Trp-Pro cis peptide bonds observed in the native state of proteins. In the model peptides the percentage of the cis proline conformer is 21% GYPG while it is 17% for GFPG. This difference is considerably smaller than the almost three to one preponderance observed for cis Tyr-Pro peptide bonds vs cis Phe-Pro peptide bonds in the protein database.

Deuterium↗
PubMed1996

Variation in H-2K(k) peptide motif revealed by sequencing naturally processed peptides from T-cell hybridoma class I molecules.

Class I major histocompatibility complex (MHC) molecules interact with a diverse array of self and foreign peptides, displaying them on the cell surface and providing an extracellular indication of intracellular invasion. The most clearly defined role for these class I/peptide complexes is to cause effector responses upon binding to antigen-specific receptors of cytotoxic T cells. We have characterized the mouse thymoma/rat V beta 8.2+ T-cell hybridoma C14/BW12-12A1 by fluorescence-activated cell sorting analysis and have used immunoaffinity chromatography to purify class I molecules from these cells. The peptides bound to the class I molecules were fractionated by high-performance liquid chromatography and sequenced. Self-peptide mixtures eluted from the mouse H-2Kk class I allele revealed a dominant primary sequence motif, with a carboxyl-terminal residue that appeared to be invariantly valine and a secondary or auxiliary anchor residue at position 2 that could be either glutamate or proline. The majority of naturally processed peptide ligands appeared to be octamers. Although peptides eluted off H-2Kk molecules from tissue derived from a number of different inbred mouse strains also appeared to be octamers, others have reported that isoleucine is the dominant carboxyl-terminal residue. Thus, different cell types displayed distinct differences in naturally processed peptides bound by the same class I alleles. The variation in naturally processed peptides loaded onto the same class I allele most likely reflects the nature of the pool of peptides within the cell available for loading class I molecules.

Alleles↗
PubMed2007

Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis.

The study of conformational transitions of peptides has obtained considerable attention recently because of their importance as a molecular key event in a variety of degenerative diseases. However, the study of peptide self-assembly into beta-sheets and amyloid beta (Abeta) fibrils is strongly hampered by their difficult synthetic access and low solubility. We have recently developed a new concept termed switch-peptides that allows the controlled onset of polypeptide folding and misfolding at physiologic conditions. As a major feature, the folding process is initiated by chemically or enzyme triggered O,N-acyl migration in flexible and soluble folding precursors containing Ser- or Thr-derived switch (S)-elements. The elaborated methodologies are exemplified for the in situ conversion of NPY- and Cyclosporine A-derived prodrugs, as well as for the onset and reversal of alpha and beta conformational transitions in Abeta peptides. In combining orthogonally addressable switch-elements, the consecutive switching on of S-elements gives new insights into the role of individual peptide segments (hot spots) in early processes of polypeptide self-assembly and fibrillogenesis. Finally, the well-known secondary structure disrupting effect of pseudoprolines (PsiPro) is explored for its use as a building block (S-element) in switch-peptides. To this end, synthetic strategies are described, allowing for the preparation of PsiPro-containing folding precursors, exhibiting flexible random-coil conformations devoid of fibril forming propensity. The onset of beta-sheet and fibril formation by restoring the native peptide chain in a single step classify PsiPro-units as the most powerful tool for inhibiting peptide self-assembly, and complement the present methodologies of the switch-concept for the study of fibrillogenesis.

Amyloid↗
PubMed1994

Identification of an HLA-DQ2 peptide binding motif and HLA-DPw3-bound self-peptide by pool sequencing.

Molecules of the major histocompatibility complex (MHC) present antigenic peptides to T cells. Sequencing peptide pools eluted from MHC class I molecules has established allele-specific peptide binding motifs. We applied pool sequencing to analyze human MHC class II-bound peptides and found that HLA-DQ2-eluted peptides predominantly contained lysine, isoleucine, and phenylalanine at relative position i, i + 3 and i + 8, respectively. These residues putatively represent anchor residues for MHC binding. Analysis of a heterogeneous HLA-DPw3/DPw4-eluted peptide pool yielded a sequence matching an epitope from the endogenous enzyme glyceraldehyde-3-phosphate dehydrogenase. This self-peptide and a partially identical, known allo-epitope bound specifically to DPw3 and DR13 molecules, suggesting the sharing of a binding motif. In particular, the presence of an arginine at relative position 4 appeared important for binding to these HLA class II specificities. Thus, pool sequencing is applicable for the analysis of MHC class II-eluted peptides.

Amino Acid Sequence↗
PubMed1995

Modulation of peptide binding by HLA-B27 polymorphism in pockets A and B, and peptide specificity of B*2703.

The results in this study address three aspects of peptide binding to the disease-associated antigen HLA-B27 and its modulation by polymorphism: the contribution of major anchor residues 2 and 9, the role of pocket B polymorphism in modulating peptide specificity, and the binding properties of B*2703, a subtype not found to be associated with spondyloarthropathy. Synthetic analogs of peptides naturally presented by B*2705 were used to demonstrate that residue 2 is essential, since Ala2 analogs bound marginally to B*2705, but the specificity of B*2705 for Arg2 is not absolute, and show that the contribution of basic residue 9 to binding was significant, but less than Arg2. The effect of single mutations in the B pocket was to decrease or--with the Glu > Met-45 mutation--totally shift pocket B specificity for Arg2 towards other residues at this position. This was shown by quantitating the relative binding of Gln2 and Ala2 analogs, and by pool-sequencing of the peptides bound in vivo to these mutants. Peptides naturally presented by B*2705 apparently bound with a lower affinity to pocket A variants with altered hydrogen bonding to the peptide N terminus, including B*2703. Binding of peptide analogs with changes at positions 2 or 9 suggested that in B*2703 pocket A, interactions are weaker and pocket B interactions are stronger than in B*2705. This can be explained by the effect of the unique His59 change in B*2703 in both pockets. Thus, B*2703 is probably the HLA-B27 sub-type with the most stringent specificity for the Arg2 peptide motif.

Amino Acid Sequence↗
PubMed2004

A novel DNA methyltransferase I-derived peptide eluted from soluble HLA-A*0201 induces peptide-specific, tumor-directed cytotoxic T cells.

MHC peptides derived from tumor-associated antigens (TAAs) can serve as the basis for the development of immunotherapeutics to treat human malignancies. Previously, we identified novel HLA-A*0201 (HLA-A2)-restricted peptides recovered from soluble HLA molecules secreted by human tumor cell lines, transfected with truncated genes of HLA-A2 and HLA-B7. Here, 4 candidate peptides eluted from soluble HLA-A2 were selected on the basis of their precursor proteins being TAAs. Peptide p1028 (GLIEKNIEL), derived from DNA methyltransferase I (DNMT-1), which is overexpressed in various human tumors, showed the highest affinity to HLA-A2 and was relatively abundant in the sMHC/peptide complexes of all transfected breast, ovarian and prostate cancer cell lines. Peptide p1028-specific CTLs were generated in vitro and shown to efficiently lyse not only target cells pulsed with the peptide but also HLA-A2-positive breast cancer cell lines MDA-231 and MCF-7. The peptide induced IFN-gamma production in CTLs, which were selectively stained by a p1028 tetramer. Since DNMT-1 is a widely expressed tumor-associated enzyme, the novel DNMT-1-derived, HLA-A2-restricted peptide GLIEKNIEL identified here may provide a suitable candidate for a therapeutic cancer vaccine.

Breast Neoplasms↗
PubMed2006

Deviation from the mobile proton model in amino-modified peptides: implications for multiple reaction monitoring analysis of peptides.

The study of peptide fragmentation is important to the understanding of chemical processes occurring in the gas phase and the more practical concern of peptide identification for proteomic analysis. Using the mobile proton model as a framework, we explore the effect of amino-group modifications on peptide fragmentation. Three aldehydes are used to transform the peptides' primary amino groups into either a dimethylamino or a heterocyclic structure (five- or six-membered). The observed fragmentation patterns deviate strongly from those observed for the analogous underivatised peptides. In particular, the a1 ion is the base peak in most tandem mass spectra of the derivatised peptides. The a1 ion intensity depends strongly on the N-terminal amino acid, with tyrosine and phenylalanine having the strongest enhancement. Despite the change in fragmentation patterns of the derivatised peptides, they still provide high-quality tandem mass spectra that, in many cases, are more amenable to database searching than the spectra of underivatised peptides. In addition, the reliable presence of the a1 ion facilitates rapid quantitative measurements using the multiple reaction monitoring approach.

Aldehydes↗
PubMed1995

The GGNG peptides: novel myoactive peptides isolated from the gut and the whole body of the earthworms.

Three novel bioactive peptides, which were structurally related to each other, were purified and chemically identified from two species of the earthworms, Eisenia foetida and Pheretima vittata. One peptide was isolated from the gut tissue of E. foetida, and the other two were purified from the whole body of E. foetida and P. vittata, respectively. These peptides consisted of 17 or 18 amino acid residues and were named GGNG peptides after their unique, common structure of the C-termini. These GGNG peptides augmented both tension and frequency of spontaneous contractions of isolated gut preparations of E. foetida, and also elicited contractions of other annelidan tissues such as the polychaete esophagus and the leech vagina. However, they showed no activity on molluscan or arthropodan tissues, suggesting that GGNG peptides may be peculiar to annelids. No peptides homologous to GGNG peptides have been known so far in any living organisms.

Amino Acid Sequence↗
PubMed1994

Comparison of properties of murine monoclonal anti-idiotypic antibodies generated with idiotype-bearing monoclonal antibodies to myelin basic protein peptides or their complementary peptides.

The present study was undertaken to compare the features of monoclonal antibody (mAb) anti-idiotope (Id) induced by complementary peptides, synthesized on the basis of inverted hydropathy for a myelin basic protein (MBP) peptide, or by conventional methodology using Id-bearing antibodies to the same MBP peptide as immunogen. The six reagents studied consisted of mAbs reactive with MBP peptide acetyl 1-9 and MBP peptide 80-89 and anti-Id reagents against these two mAbs prepared by either the complementary peptide or the conventional approach. ELISA, immunoblotting, immunoinhibition of hybridoma cell production of Id-bearing mAb to MBP, and FACS indicated that the anti-Ids generated by either technique were similar although existing in a range reflecting biologic phenomena. mAbs anti-Id prepared by either method continued to show an IgM isotype preference, possibly related to technical considerations, and continued to recognize a cross-reactive Id on the kappa light chain of the mAbs to MBP peptides acetyl 1-9 and 80-89. There was no indication that the anti-Ids prepared by the complementary peptide approach were restrictive or selective in a manner different from those made by the conventional approach.

Amino Acid Sequence↗
PubMed1999

Immunogenicity of tumor peptides: importance of peptide length and stability of peptide/MHC class II complex.

Nonameric P815AB, a cytotoxic-T-lymphocyte-defined minimal core peptide encoded by the murine mastocytoma gene P1A, fails to initiate CD4+ cell-dependent reactivity in vivo to class-I-restricted epitopes when mice are administered peptide-pulsed dendritic cells. Effective immunization requires T helper effects, such as those mediated by coimmunization with class-II-restricted (helper) peptides or by the use of recombinant interleukin-12 (rIL-12). Although P815AB does possess class-II-restricted epitopes, they are likely suboptimal, resulting in poor affinity and/or stability of MHC/P815AB complexes and inadequate activation of the antigen-presenting cell function of dendritic cells. The present study has examined a series of longer, P815AB-centered peptides (11-14 amino acids in length, all P1A-encoded) for their ability to initiate CD4+ and CD8+ cell-mediated responses to the nonamer in vivo, their ability to bind class II MHC in vitro, and their ability to assemble class II molecules stably. By means of a class-I-restricted skin test assay in mice receiving peptide-pulsed dendritic cells, we found that a 12-mer and a 13-mer effectively immunized against the core P815AB peptide, and that this correlated with IL-2 production in vitro by CD4+ cells in response to the nonamer. In vitro studies, involving affinity-purified class II molecules, showed that the capacity to assemble class II molecules stably, more than the affinity for class II MHC, correlated with the ability of the different P815AB peptides to prime the host to the core peptide seen by the T cells.

Amino Acid Sequence↗
PubMed1991

Epitope mapping employing immobilized synthetic peptides. How specific is the reactivity of these peptides with antiserum raised against the parent protein?

Peptides synthesized onto polyethylene pins can be directly used to map the antigenic structure of proteins by ELISA (Geysen et al., 1987, J. Immunol. Methods 102, 259-274). The specificity of the reaction between anti-cytochrome c antibodies (IgG) and pin-bound hexapeptides of cytochrome c was tested using a competitive ELISA in which free and pin-bound peptides competed for the antibody. Competition was specific for many of the pin-bound peptides: only free peptides having the same sequence as the pin-bound peptides were able to compete for antibody-binding. However, non-specific reactivity was observed with pin-bound peptides whose sequence corresponded to the N terminal segment of cytochrome c. This segment is predicted to be particularly antigenic because of its high mobility and the nature of its amino acid sequence. In one case no competition by the free peptide could be observed even though the pin-bound peptide reacted strongly with anti-cytochrome c antibodies.

Animals↗
PubMed1994

Cross-reactivity of monoclonal antibodies to a chimeric V3 peptide of HIV-1 with peptide analogues studied by biosensor technology and ELISA.

The reactivity of monoclonal antibodies (Mabs) raised against a cyclic peptide representing a chimeric V3 loop of HIV-1 gp120 with different peptide analogues was studied with a biosensor system (BIAcore) and by ELISA. In both assays, the Mabs cross-reacted extensively with the V3 regions of different HIV-1 strains and recognized the cyclic form of the peptide immunogen better than its linear form. The highest degree of cross-reactivity was observed with peptides that shared a Lys312 with the chimeric sequence. Dissociation rate constants of ten Mabs measured with the BIAcore with respect to different peptides increased with increasing numbers of substitutions in the flanking regions of the V3 tip sequence Gly Pro Gly Arg. Immobilization of the cyclic peptide on the sensor chip via a thiol group added near the end of the loop structure preserved the conformation of the peptide. In view of the good correlation between the BIAcore and ELISA results, biosensor data should be useful for selecting peptides to be used in diagnostic solid phase assays.

Amino Acid Sequence↗
PubMed1993

The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2.

Complexes of five peptides (from HIV-1, influenza A virus, HTLV-1, and hepatitis B virus proteins) bound to the human class I MHC molecule HLA-A2 have been studied by X-ray crystallography. While the peptide termini and their second and C-terminal anchor side chains are bound similarly in all five cases, the main chain and side chain conformations of each peptide are strikingly different in the center of the binding site, and these differences are accessible to direct TCR recognition. Each of the central peptide residues is seen to point up for some bound peptides, but down or sideways for others. Thus, although fixed at its ends, the structure of an MHC-bound peptide appears to be a highly complex function of its entire sequence, potentially sensitive to even small sequence differences. In contrast, MHC structural variation is relatively limited. These results offer a structural framework for understanding the role of nonanchor peptide side chains in both peptide-MHC binding affinity and TCR recognition.

Amino Acid Sequence↗
PubMed1996

Identification of peptides mimicking the antigenicity and immunogenicity of conformational epitopes on Japanese encephalitis virus protein using synthetic peptide libraries.

Monoclonal antibodies (mAbs) N.03 and N.08 that recognize conformational epitopes on the prM protein of Japanese encephalitis virus (JEV) were analyzed to identify their peptide ligands by using a novel approach that combined two different synthetic peptide libraries. Immunoscreening of a library containing 20(5) sequences of pentapeptides revealed that the ligands for N.03 and N.08 had motif sequences, (Y/W/F)GG(I/L/M) and (N/Q)WY(D/E), respectively. To select higher-affinity ligands, we synthesized and screened another type of library with 20 peptide mixtures that were based on the identified motif, where only one amino acid position was defined; and the process was reiterated for the remaining undefined positions. Consequently, the peptides YGGIYMNG and QWYDDR were identified as peptide ligands of N.03 and N.08, respectively. These peptides bound specifically to the antigen-combining sites of the mAbs as confirmed by competitive binding assays. Mouse antisera directed against the peptide YGGIYMNG specifically recognized JEV, while those against QWYDDR did not. These data demonstrated that peptide ligands which reproduce or mimic the immunogenicity as well as the antigenicity of conformational epitopes can be at least partly identified using this approach. This approach may be useful for analyzing conformational epitopes, which are generally difficult to characterize, and might provide a step toward vaccine development when applied to protective mAbs.

Antigens, Viral↗
PubMed1994

"Bridged" peptide of fibrinogen binds to platelets activated by RGD peptide as well as by ADP.

We have evaluated the binding of a bridged peptide of Y-HHLGGAKQAGDV(G)9RGDS to RGDS-activated platelets. The bridged peptide saturably bound to platelets activated by RGDS peptide and by ADP with binding sites of 38,600 +/- 4800 molecules/platelet (Kd = 8.9 +/- 1.3 x 10(-7) M) and 43,600 +/- 9,200 molecules/platelet (Kd = 3.1 +/- 0.5 x 10(-7) M), respectively. Native fibrinogen inhibited the binding of the bridged peptide to platelets activated by RGDS peptide and by ADP with IC50s of 1.2 +/- 0.4 microM and 1.8 +/- 0.6 microM, respectively. In addition, the RGDS peptide and the dodecapeptide (gamma 400-411; HHLGGAKQAGDV) completely inhibited the binding of the bridged peptide to platelets activated by RGDS peptide with IC50s of 32 +/- 2.6 microM for RGDS and 102 +/- 4.1 microM for gamma 400-411, respectively. The anti-GPIIb/IIIa monoclonal antibody, LJ-CP8, also inhibited these bindings. The IC50s were 75 +/- 8.6 micrograms/ml for RGDS activation and 56 +/- 6.3 micrograms/ml for ADP stimulation. These results suggest that the flexible hinge region may allow assumption of the appropriate structure in the presence of the receptor complex. It indicates that both RGDS and agonist stimulation may play an important role in inducing activation of platelets that results in further platelet aggregation and tight thrombus formation.

Adenosine Diphosphate↗
PubMed1993

Vasoactive intestinal peptide release and L-citrulline production from isolated ganglia of the myenteric plexus: evidence for regulation of vasoactive intestinal peptide release by nitric oxide.

Vasoactive intestinal peptide release and L-[3H]citrulline production were examined in ganglia isolated from the myenteric plexus of guinea-pig intestine. The nicotinic agonist, 1,1-dimethyl-4-phenylpiperizinium stimulated vasoactive intestinal peptide release and L-[3H]citrulline production; the latter was considered an index of nitric oxide production. Both vasoactive intestinal peptide release and L-[3H]citrulline production were abolished by tetrodotoxin, hexamethonium, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Inhibition of vasoactive intestinal peptide release by NG-nitro-L-arginine was reversed by L-arginine but not by D-arginine. Exogenous nitric oxide stimulated vasoactive intestinal peptide release whereas exogenous vasoactive intestinal peptide had no effect on L-[3H]citrulline production. The pattern of stimulation by nitric oxide and inhibition by NG-nitro-L-arginine implied that vasoactive intestinal peptide release is facilitated by and may be dependent on nitric oxide production. Consistent with this notion, vasoactive intestinal peptide release in response to either 1,1-dimethyl-4-phenylpiperizinium or nitric oxide was abolished by KT 5823, an inhibitor of cyclic GMP-dependent protein kinase activity and by LY83583, an inhibitor of soluble guanylate cyclase activity. The study provides the first direct evidence of nitric oxide production from enteric ganglia.

Alkaloids↗