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PubMed1992

Iron uptake and molecular recognition in Pseudomonas putida: receptor mapping with ferrichrome and its biomimetic analogs.

The presence of an Fe(3+)-ferrichrome uptake system in fluorescent Pseudomonas spp. was demonstrated, and its structural requirements were mapped in Pseudomonas putida with the help of biomimetic ferrichrome analogs. Growth tests, 55Fe3+ uptake, and competition experiments demonstrated that the synthetic L-alanine derivative B5 inhibits the action of ferrichrome but does not facilitate Fe3+ transport, while the enantiomeric D-Ala derivative B6 fails to compete with ferrichrome. Contraction of the molecule's envelope by replacing L-Ala by glycine provided a synthetic carrier, B9, which fully simulates ferrichrome as a growth promoter. Sodium azide inhibited 55Fe3+ uptake of the Gly derivative B9, suggesting an active transport process. These data demonstrate the chiral discrimination of the ferrichrome receptor and its sensitivity to subtle structural changes. They further confirm that receptor binding is a necessary but not sufficient condition for Fe3+ uptake to occur and suggest that binding to the receptor and transport proteins might rely on different recognition patterns.

Bacterial Outer Membrane Proteins↗
PubMed2006

Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity.

Recognition of specific pathogen associated molecular patterns (PAMPs) is mediated primarily by members of the Toll-like receptor (TLR) family. Stimulation through these receptors results in quantitative and qualitative changes in antigen presentation and cellular activation, thereby linking innate and adaptive immunity. Consequently, the incorporation of TLR-ligands into vaccines could result in more potent and efficacious vaccines. To test this hypothesis, we employed a recombinant fusion protein strategy using the TLR5 ligand flagellin fused to specific antigens to promote protective immunity. These purified recombinant fusion proteins demonstrated potent TLR5-specific NF-kappaB dependent activity in vitro. Immunization of mice with the recombinant-flagellin-OVA fusion protein STF2.OVA resulted in potent antigen-specific T and B cell responses that were equal to or better than responses induced by OVA emulsified in Complete Freund's adjuvant. These included rapid and consistent antigen-specific IgG(1) and IgG(2a) antibody responses that were detectable within 7 days of immunization, and the development of protective CD8 T cell responses. Moreover, the enhanced immunogenicity to OVA is dependant on the direct fusion to flagellin, as co-delivery of OVA with flagellin unlinked failed to augment antigen-specific responses in vivo. Similar results were obtained using a recombinant fusion protein comprised of flagellin and a novel polypetide sequence containing two immuno-protective epitopes derived from the Listeria monocytogenes antigens p60 and listeriolysin O. Animals immunized with this recombinant protein demonstrated significant antigen-specific CD8 T cell responses and protection upon challenge with virulent L. monocytogenes. We conclude that immunization with PAMP:antigen fusion proteins induce rapid and potent antigen-specific responses in the absence of supplemental adjuvants. Collectively our data demonstrate that PAMP:antigen fusion proteins offer significant promise for developing recombinant protein vaccines.

Animals↗
PubMed2002

Recognition of lipopeptides by Toll-like receptors.

Toll-like receptors (TLRs) recognize specific molecular patterns present only in micro-organisms and thereby activate innate immune cells. TLR2 is essential for the recognition of peptidoglycan and lipoprotein/lipopeptides. Lipoprotein/lipopeptides are observed in cell walls of a variety of micro-organisms. Host immune cells recognize the specific patterns of lipoprotein/lipopeptides through the association of TLR2 with other TLRs. TLR1 and TLR6 are highly homologous to TLR2 in structure. TLR6-deficient mice showed an impaired response to mycoplasmal lipopeptides that are diacylated, whereas TLR1-deficient mice were defective in their response to bacterial lipopeptides that are triacylated. TLR2-deficient mice did not show any inflammatory response to either type of lipopeptide. The functional association of TLR2 with TLR1 or TLR6 has been demonstrated. Thus, TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl lipopeptides through interaction with TLR2.

Animals↗
PubMed1995

NK cell recognition of MHC class I. NK cells are sensitive to peptide-binding groove and surface alpha-helical mutations that affect T cells.

NK cells directly or indirectly recognize MHC class I molecules, but the exact structures recognized remain poorly defined. We address the hypothesis that NK cells, like T cells, directly contact peptide/MHC class I complexes. This hypothesis predicts that NK-mediated killing is inhibited by amino acid substitutions in the MHC class I peptide-binding groove and in solvent-accessible alpha-helical residues proposed to contact the TCR. In our model system, target cell HLA-B*0702 inhibited killing by unstimulated peripheral blood NK cells. NK-mediated killing was increased significantly by 6 of 11 peptide-binding groove mutations and 6 of 12 TCR contact site mutations, but only 1 of 6 mutations outside these sites. Many of the mutations that inhibited NK-mediated killing prohibited killing by 12 alloreactive CTL clones. These data suggest that NK receptors directly contact HLA-B*0702, focusing on the peptide-binding groove and surrounding alpha-helices. NK cell lines exhibited multiple HLA recognition patterns, which is consistent with nonuniform expression of MHC receptors by NK cells. We propose that NK cells, like alpha beta T cells and some anti-MHC Abs, directly or indirectly recognize MHC-bound peptides.

Binding Sites↗
PubMedDate not supplied

A biophysical model of synaptic delay learning and temporal pattern recognition in a cerebellar Purkinje cell.

It has been suggested that information in the brain is encoded in temporal spike patterns which are decoded by a combination of time delays and coincidence detection. Here, we show how a multi-compartmental model of a cerebellar Purkinje cell can learn to recognise temporal parallel fibre activity patterns by adapting latencies of calcium responses after activation of metabotropic glutamate receptors (mGluRs). In each compartment of our model, the mGluR signalling cascade is represented by a set of differential equations that reflect the underlying biochemistry. Phosphorylation of the mGluRs changes the concentration of receptors which are available for activation by glutamate and thereby adjusts the time delay between mGluR stimulation and voltage response. The adaptation of a synaptic delay as opposed to a weight represents a novel non-Hebbian learning mechanism that can also implement the adaptive timing of the classically conditioned eye-blink response.

Action Potentials↗
PubMed2005

How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals.

Innate immune detection of pathogens relies on specific classes of microbial sensors called pattern-recognition molecules (PRM). In mammals, such PRM include Toll-like receptors (TLRs) and the intracellular proteins NOD1 and NOD2, which belong to the family of Nod-like receptors (NLRs). Over the last decade as these molecules were discovered, a function in innate immunity has been assigned for the majority of them and, for most, the microbial motifs that these molecules detect were identified. One of the next challenges in innate immunity is to establish a better understanding of the complex interplay between signaling pathways induced simultaneously by distinct PRMs and how this affects tailoring first-line responses and the induction of adaptive immunity to a given pathogen.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity.

Signaling by the Eph family of receptor tyrosine kinases (RTKs) is complex, because they can interact with a variety of intracellular targets, and can potentially induce distinct responses in different cell types. In NG108 neuronal cells, activated EphB2 recruits p120RasGAP, in a fashion that is associated with down-regulation of the Ras-Erk mitogen-activated kinase (MAPK) pathway and neurite retraction. To pursue the role of the Ras-MAPK pathway in EphB2-mediated growth cone collapse, and to explore the biochemical and biological functions of Eph receptors, we sought to re-engineer the signaling properties of EphB2 by manipulating its regulatory motifs and SH2 binding sites. An EphB2 mutant that retained juxtamembrane (JM) RasGAP binding sites but incorporated a Grb2 binding motif at an alternate RasGAP binding site within the kinase domain had little effect on basal Erk MAPK activation. In contrast, elimination of all RasGAP binding sites, accompanied by the addition of a Grb2 binding site within the kinase domain, led to an increase in phospho-Erk levels in NG108 cells following ephrin-B1 stimulation. Functional assays indicated a correlation between neurite retraction and the ability of the EphB2 mutants to down-regulate Ras-Erk MAPK signaling. These data suggest that EphB2 can be designed to repress, stabilize, or activate the Ras-Erk MAPK pathway by the manipulation of RasGAP and Grb2 SH2 domain binding sites and support the notion that Erk MAPK regulation plays a significant role in axon guidance. The behavior of EphB2 variants with mutations in the JM region and kinase domains suggests an intricate pattern of regulation and target recognition by Eph receptors.

Amino Acid Sequence↗
PubMed2005

Pathogen recognition with Toll-like receptors.

The innate immune system is an evolutionarily conserved system of defense against microbial infections. The family of Toll-like receptors is a major class of receptors that sense molecular patterns associated with a broad range of pathogens including bacteria, viruses, fungi and protozoa. Following pathogen recognition, Toll-like receptors initiate intracellular signal transduction that results in the expression of genes involved in inflammation, antiviral responses and maturation of dendritic cells. Individual Toll-like receptors activate common and unique transcription factors through different signaling pathways to drive specific biological responses against microorganisms.

Animals↗
PubMed1993

Surface motifs by a computer vision technique: searches, detection, and implications for protein-ligand recognition.

We describe the application of a method geared toward structural and surface comparison of proteins. The method is based on the Geometric Hashing Paradigm adapted from Computer Vision. It allows for comparison of any two sets of 3-D coordinates, such as protein backbones, protein core or protein surface motifs, and small molecules such as drugs. Here we apply our method to 4 types of comparisons between pairs of molecules: (1) comparison of the backbones of two protein domains; (2) search for a predefined 3-D C alpha motif within the full backbone of a domain; and in particular, (3) comparison of the surfaces of two receptor proteins; and (4) comparison of the surface of a receptor to the surface of a ligand. These aspects complement each other and can contribute toward a better understanding of protein structure and biomolecular recognition. Searches for 3-D surface motifs can be carried out on either receptors or on ligands. The latter may result in the detection of pharmacophoric patterns. If the surfaces of the binding sites of either the receptors or of the ligands are relatively similar, surface superpositioning may aid significantly in the docking problem. Currently, only distance invariants are used in the matching, although additional geometric surface invariants are considered. The speed of our Geometric Hashing algorithm is encouraging, with a typical surface comparison taking only seconds or minutes of CPU time on a SUN 4 SPARC workstation. The direct application of this method to the docking problem is also discussed. We demonstrate the success of this method in its application to two members of the globin family and to two dehydrogenases.

Alcohol Dehydrogenase↗
PubMed2000

A horseshoe crab receptor structurally related to Drosophila Toll.

Innate immunity against microbial pathogens relies on the pattern recognition of cell wall components on invading microbes. Recent evidence has shown that a mammalian Toll-like receptor (TLR) is activated by bacterial lipopolysaccharides (LPS). The innate immunity in invertebrates is also triggered by LPS, as seen in the hemolymph coagulation in horseshoe crab. We report the cloning of a TLR from the Japanese horseshoe crab Tachypleus tridentatus. A cDNA coding for Tachypleus Toll was isolated from a hemocyte cDNA library and the open reading frame codes for a proprotein including a signal sequence. Like Drosophila Toll, Tachypleus Toll is a type I transmembrane protein with an extracellular domain consisting of two leucine-rich repeats flanked by two cystein-rich clusters and a cytoplasmic domain exhibiting striking similarity with the cytoplasmic domain of interleukin-1 receptor. Tachypleus Toll is most similar to Drosophila Toll in the domain architecture and the overall length.

Animals↗
PubMed2005

A novel pesticide-induced conformational state of the oestrogen receptor ligand-binding domain, detected by conformation-specific peptide binding.

The diverse effects of different natural and synthetic oestrogen receptor ligands depend on induction of different receptor conformations, allowing differential interactions with other transcription factors. Different conformations of the oestrogen receptor ligand binding domains can be monitored by conformation-specific binding to peptides selected from phage-displayed peptide libraries. We now report that a group of chlorinated pesticides, including 2,4-dichlorodiphenyl-dichloroethylene, induces a peptide recognition pattern different from those induced by any one of the classical oestrogen receptor ligands. The pesticide-complexed oestrogen receptors recognized peptides reacting with the receptors complexed both with the natural oestrogen 17beta-oestradiol and with the synthetic partial antagonist 4-hydroxy-tamoxifen, respectively, indicating that the pesticide-induced conformation shares features with both the 17beta-oestradiol- and the 4-hydroxy-tamoxifen-induced conformations. The substitution H524A in the ligand binding domain conferred the pesticide-specific peptide recognition pattern and transactivation activity to the oestradiol- and the 4-hydroxy-tamoxifen-complexed receptors, indicating that one important determinant of the pesticide-induced conformation is a lack of stabilisation of any one particular receptor conformation by ligand interaction with H524, which is known to interact with both oestradiol and 4-hydroxy-tamoxifen. Thus, peptide binding analyses of oestrogen receptor conformations induced by environmental endocrine disruptors can give novel information about molecular mechanisms of oestrogen action in general.

Amino Acid Substitution↗
PubMed1989

Demonstration of muscarinic acetylcholine receptor-like immunoreactivity in the rat forebrain and upper brainstem.

The distribution of muscarinic acetylcholine receptor protein (mAChR) in the rat forebrain and upper brainstem was described by using a monoclonal antibody (M35) raised against mAChR purified from bovine forebrain homogenates. A method is investigated for light microscopic (LM) and electronmicroscopic (EM) immunocytochemical visualization of reactivity to mAChR-proteins. Putative cholinoceptive neurons including their dendrites were found immunoreactive in the cortical mantle, hippocampus, basal ganglia, amygdala, thalamus and several midbrain regions. In the neocortex, immunoprecipitate with M35 was mainly present in layer 5 pyramidal cells, some layer 3 pyramidal neurons and layer 2 stellate cells, all including their characteristic dendritic profiles of both basal and apical dendrites. In the hippocampus, a variety of pyramidal, granular and non-pyramidal celltypes were stained in various hippocampal cell layers, in the dentate hilus and in stratum oriens of cornu ammonis. Moreover, positively reacting cells occurred in central and lateral amygdala, all parts of the basal ganglia and ventral pallidum. The thalamus was very richly provided with labeled neurons in several nuclei but notably numerous in the ventrolateral, anteroventral and geniculate nuclei. In cortex and hippocampus also some staining of astrocytes occurred. Electron microscopic study of the intracellular distribution of M35 immunoreactivity in all cases showed dense precipitates in the soma cytoplasm in close association with the golgi apparatus, but conspicuous absence near the endoplasmic reticulum. Immunoprecipitate can be followed within the dendritic tree along the microtubular transport system, up to proximal and distal postsynaptic membrane positions, apposing non labeled presynaptic endings. Muscarinic receptor subtype recognition by M35 will be discussed by comparing M35 distribution with cholinergic innervation patterns, muscarinic receptor ligand binding studies and localization of muscarinic receptor subtype mRNAs.

Animals↗
PubMedDate not supplied

Detection of metastasis-associated differences for receptors of glycoconjugates (lectins) in histomorphologically unchanged xenotransplants from primary and metastatic lesions of human colon adenocarcinomas.

Clinically applicable markers for tumor progression may be uncovered by selective analysis of biochemical parameters, supposedly participating in this complex process. Owing to the importance of specific protein-carbohydrate interactions in diverse biological processes, the pattern of the receptor part in this glycobiochemical recognition system, the sugar receptors (lectins), conceivably reflects biological properties of tumor cells in glycobiochemical terms. Therefore, we established and characterized xenografts from surgically removed specimens of a human primary colon adenocarcinoma and its metastatic lesions to liver of the same patient and of a histomorphologically similar primary colon adenocarcinoma of another patient in nude mice. Xenotransplantation and subsequent glycobiochemical analysis of material from early passages with a standardized procedure had been preferred to cell culture in monolayer on account of maintenance of a higher degree of organized histotypic assembly. Despite histomorphological similarities, the sugar receptor profile revealed significant differences in tumor-tumor and tumor-metastasis comparison, especially for alpha- and beta-galactoside-binding proteins. Tumor-metastasis differences were substantiated by a second successfully xenotransplanted pair of specimens. Comprehensive expansion of these initial data may eventually lead to desirable functional correlations with the different biological properties of histomorphologically similar primary colon adenocarcinomas and of the metastatic phenotype and to a rational development of therapeutic modalities to restrict tumor growth and spread.

Adenocarcinoma↗
PubMed2007

Bacterial flora of the female genital tract: function and immune regulation.

The use of non-culture gene amplification techniques has improved our understanding of the composition of the vaginal bacterial ecosystem. In most healthy women in the reproductive period the predominant vaginal bacteria are one or more of the following species of Lactobacillus: L. crispatus, L. iners and L. gasseri. However, in other apparently healthy women lactobacilli may be deficient or absent, being replaced by other lactic-acid-producing bacteria: Atopobium, Megasphaera and/or Leptotrichia species. Infection and/or proliferation of pathogenic bacteria in the vagina is suppressed by lactic acid production, bacteria-generated antimicrobial products, and the local activities of the innate and cell-mediated immune systems. Vaginal epithelial cells produce a range of compounds with antimicrobial activities. These cells also possess membrane-bound Toll-like receptors that recognize pathogen-associated molecular patterns. Recognition leads to pro-inflammatory cytokine production and antigen-specific immunity. Local production of IgG and IgA antibodies can also be initiated in the endocervix and vagina in response to infection.

Female↗
PubMed2002

Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both.

BACKGROUND: Exposure to various microbial products in early life reduces the risk of atopy. Such exposure induces downregulation of T(H)2 allergy-biased responses by means of pattern recognition molecules, such as CD14, an LPS receptor. OBJECTIVE: We sought to determine whether infant and maternal levels of soluble CD14 (sCD14) are associated with the atopic outcomes of infants. METHODS: Levels of sCD14 in plasma, amniotic fluid, and breast milk were measured with a specific ELISA in different cohorts. Expression of toll-like receptors in the fetal gut was examined by using RT-PCR. RESULTS: Soluble CD14 levels increased during fetal development and postnatally, attaining adult levels by around 4 months of age, with an overshoot of adult levels from 6 months of age. There was no difference in plasma sCD14 levels at birth of children with a high compared with those with a low risk of development of atopy. Amniotic fluid sCD14 levels at midgestation (16-17 weeks) were significantly lower when the child was subsequently atopic (P <.05). Soluble CD14 levels in breast milk collected 3 months postpartum were significantly lower in children with eczema at 6 months of age, irrespective of whether they were atopic (P =.003). Transcripts for toll-like receptor 4, which would enable transmembrane signaling for LPS/sCD14 complexes, were expressed within fetal gut and skin. CONCLUSION: Exposure to reduced levels of sCD14 in the fetal and neonatal gastrointestinal tract is associated with the development of atopy, eczema, or both. Thus the exogenous supply of sCD14 might influence immunologic reactivity both locally and systemically in early life and thereby influence disease outcome.

Amniotic Fluid↗
PubMed2003

Host innate defenses in the lung: the role of cytokines.

PURPOSE OF REVIEW: The lung has a unique relationship with the environment. Through evolution the lung has developed strategies to defend itself from microbial invasion. As we encounter increasing multidrug-resistant microorganisms, we need to further our knowledge of innate defense systems in order to design novel strategies to deal with these microbes without inducing over-exuberant inflammation and lung injury. RECENT FINDINGS: The development of lung innate immunity requires microbial molecular pattern recognition by the recently described Toll like receptors, the release of early response cytokines that further activate the 'master switch', nuclear factor-kappaB, leading to amplified host defense to invading microbes. A balance of Type 1 and Type 2 cytokines modulates the intensity of innate immunity. Cytokines/chemokines orchestrate the polarization and transition of innate to adaptive immunity. SUMMARY: The elucidation of the pathways involved in innate immunity and factors controlling the transition to adaptive immunity will improve our understanding of the host response to infection and improve our ability to design new therapies for the treatment of infectious disease.

Chemokines↗
PubMed1996

The 1.8 A crystal structure of human cathepsin G in complex with Suc-Val-Pro-PheP-(OPh)2: a Janus-faced proteinase with two opposite specificities.

The crystal structure of human neutrophil cathepsin G, complexed with the peptidyl phosphonate inhibitor Suc-Val-Pro-PheP-(OPh)2, has been determined to a resolution of 1.8 A using Patterson search techniques. The cathepsin G structure shows the polypeptide fold characteristic of trypsin-like serine proteinases and is especially similar to rat mast cell proteinase II. Unique to cathepsin G, however, is the presence of Glu226 (chymotrypsinogen numbering), which is situated at the bottom of the S1 specificity pocket, dividing it into two compartments. For this reason, the benzyl side chain of the inhibitor PheP residue does not fully occupy the pocket but is, instead, located at its entrance. Its positively charged equatorial edge is involved in a favourable electrostatic interaction with the negatively charged carboxylate group of Glu226. Arrangement of this Glu226 carboxylate would also allow accommodation of a Lys side chain in this S1 pocket, in agreement with the recently observed cathepsin G preference for Lys and Phe at P1. The cathepsin G complex with the covalently bound phosphonate inhibitor mimics a tetrahedral substrate intermediate. A comparison of the Arg surface distributions of cathepsin G, leukocyte elastase and rat mast cell protease II shows no simple common recognition pattern for a mannose-6-phosphate receptor-independent targeting mechanism for sorting of these granular proteinases.

Amino Acid Sequence↗