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Crucifers (Brassicaceae) in 11 genera are often infected by rust fungi in the Puccinia monoica complex. Infection causes a 'pseudoflower' to form that is important for attracting insect visitors that sexually outcross the fungus. 'Pollinator' attraction is accomplished through visual floral mimicry, the presence of a nectar reward and floral fragrances. Here we used gas chromatography and mass spectrometry to identify and quantify fragrance production by these rust fungi on several Arabis hosts, and by co-occurring true flowers that share insect visitors. Fungal pseudoflowers produced distinctive floral fragrances composed primarily of aromatic alcohols, aldehydes and esters. Pseudoflower fragrances were chemically similar to noctuid-moth-pollinated flowers, such as Cestrum nocturnum and Abelia grandiflora, but were very different from host flowers, host vegetation and the flowers of coblooming, nonhost angiosperms. There was variation in the quantity and composition of fragrance profiles from different fungal species as well as within and among hosts. The evolution of scent chemistry is relatively conservative in these fungi and can be most parsimoniously explained in three steps by combining chemical data with a previously determined rDNA ITS sequence-based phylogeny. Pseudoflower scent does not appear to represent a simple modification of host floral or vegetative emissions, nor does it mimic the scent of coblooming flowers. Instead, we suspect that the unique fragrances, beyond their function as pollinator attractants, may be important in reducing gamete loss by reinforcing constancy among foraging insects.
Mol Ecol 1998 Sep
PMID:'Floral' scent production by Puccinia rust fungi that mimic flowers. 973 71

cDNA and genomic DNA clones covering the entire open reading frame (ORF) for a Plasmodium chabaudi 96V protein were isolated. From the first ATG codon the intronless gene codes for a 229-kDa protein. Antisera raised against recombinant polypeptides coded by two different regions of the gene reacted with a 240/225-kDa doublet on Western blots of parasite extracts. In immunofluorescence studies the same sera detected the antigen at the apical end of the merozoite, possibly in rhoptry organelles. In Western blotting experiments the recombinant polypeptides were recognised by antibodies induced by natural infection. A 364-amino acid residue repetitive region, based on 32 11-mer repeats divided by two 6-mer repeats into three blocks, is located in the centre of the protein. Analysis of this repetitive region led us to propose a model in which each of the three units forms an alpha-helical coiled-coil triple-helix containing a possible leucine-histidine zipper. Each unit resembles in structure the units present in spectrin. The repeat region is flanked by predicted heptad based alpha-helical coiled-coil regions, and we propose that the protein forms a dimer. The 229-kDa protein has the overall character of a cytoskeletal protein. We have named the 229-kDa protein repetitive organellar protein (ROPE) and suggest that ROPE may be involved in the process of invasion, possibly by interacting with the erythrocyte cytoskeleton, and that the leucine histidine-zipper may be involved in molecular mimicry of spectrin.
Mol Biochem Parasitol 1998 Aug 01
PMID:A Plasmodium chabaudi protein contains a repetitive region with a predicted spectrin-like structure. 974 69

Peptides as mimics of carbohydrates display a distinct advantage in vaccine design because of ease of synthesis and their inherent T cell-dependent nature as immunogens. While peptides that mimic carbohydrates have been described, it is not clear how they do so. To further our insight into structural relationships between peptide-mimics and carbohydrate structures, we have analyzed a potential recognition scheme between the murine monoclonal antibody, B3, directed against the tumor-associated antigen Lewis Y oligosaccharide and a peptide identified from phage display screening with B3. The Lewis Y core antigen is a difucosylated structure consisting of four hexose units. The B3 antibody binds to the peptide sequence APWLYGPA in which the putative sequence APWLY is critical for binding to the antibody. Not having experimental structural information for B3, the crystal structure of another anti-Lewis Y antibody, BR96, solved in complex with a nonoate methyl ester Lewis Y tetrasaccharide, provides a molecular basis for LeY antigen recognition and specificity, and how this binding relates to peptide binding. As a guide to place the APWLY motif in the B3 combining site, a fragment library was searched for analogous compounds that have the potential to bind to B3. Our modeling study shows that the B3-peptide complex shares similar recognition features for the difucosylated type 2 lactoseries' structure. This analysis provides a molecular perspective for peptide mimicry of a carbohydrate epitope.
J Mol Recognit
PMID:Molecular recognition of a peptide mimic of the Lewis Y antigen by an anti-Lewis Y antibody. 977 Jun 51

Monoclonal antibodies recognize antigens with high affinity and specificity, but the structural basis for molecular mimicry remains unclear. It is often assumed that cross-reactive antigens share some structural similarity that is specifically recognized by a monoclonal antibody. Recent studies using combinatorial libraries, which are composed of millions of sequences, have examined antibody cross-reactivity in a manner entirely different from traditional epitope mapping approaches. Here, peptide libraries were screened against an anti-carbohydrate monoclonal antibody for the identification of peptide mimics. Positional scanning libraries composed of all-l or all-d hexapeptides were screened for inhibition of monoclonal antibody HGAC 39.G3 binding to an antigen displaying N-acetyl-d-glucosamine (GlcNAc) residues on a polyrhamnose backbone. Inhibitory activity by mixtures from the all-d hexapeptide library was greater than the activity from the all-l libraries. The most active d-amino acid residues defined in each of the six positions of the library were selected to prepare 27 different individual hexapeptides. The sequence Ac-yryygl-NH2 was specifically recognized by mAb HGAC 39.G3 with a relative affinity of 300 nM when measured in a competitive binding assay. The contributions to overall specificity of the residues of the all-d peptide (Ac-yryygl-NH2) in binding to mAb HGAC 39.G3 were examined with a series of truncation, l and d-amino acid substitution, and retro analogs. Dimeric forms of the all-d peptide were recognized with tenfold to 100-fold greater affinities relative to the monomer. The all-d peptide was found to inhibit mAb HGAC 39.G3 binding to an anti-idiotype antibody with approximately 1000-fold greater affinity than GlcNAc. As demonstrated here, the study of immune recognition using combinatorial chemistry may offer new insights into the molecular basis of cross-reactivity.
J Mol Biol 1998 Nov 13
PMID:All-D peptides recognized by an anti-carbohydrate antibody identified from a positional scanning library. 979 40

For the therapy of cancer patients whose disease is positive for Carcinoembryonic Antigen (CEA), we developed an active specific immunotherapy based on the idiotypic network. The anti-idiotype monoclonal antibody (mAb), 3H1 was generated by immunization of mice with the anti-CEA mAb, 8019. 3H1 mimics CEA both functionally and structurally and acts as a surrogate for CEA. To define the minimum structural requirements for antigen mimicry by 3H1, we constructed plasmid vectors for expression of single chain Fv (scFv) variants of 3H1 in Escherichia coli. Variable heavy (VH) and variable light (VL) chain domains of 3H1 were linked by a 15 amino acid linker (Ln), (Gly4Ser)3 in two constructs, VH-Ln-VL and VL-LnVH. Ln was omitted in two constructs, VH-VL and VL-VH. Each of the scFv constructs has a tag of six His [(His)6 tag] for purification by metal chelate affinity chromatography and detection by enzyme-linked immunoabsorbent assay (ELISA). Comparisons of the binding of 8019 to purified scFv proteins by ELISA and immunoblot experiments showed that only VH-Ln-VL had significant activity. VH-Ln-VL also showed maximum inhibition of binding of 8019 to CEA. Immunization of mice with naked VH-Ln-VL and VH-Ln-VL conjugated to keyhole limpet hemocyanin induced anti-CEA antibodies in mouse sera. Sera from immunized mice inhibited the binding of 8019 to 3H1 as well as CEA. Induction of anti-CEA antibodies in the immunized mice was confirmed by flow cytometric analysis using CEA positive MC-38cea cells. These results demonstrate that for antigen mimicry of 3H1 scFv, the presence of Ln is necessary and the domain order should be VH followed by VL.
Mol Immunol 1998 Sep
PMID:Antigen mimicry by an anti-idiotypic antibody single chain variable fragment. 983 54

Ankylosing spondylitis (AS), reactive arthritis (ReA) and other related spondyloarthropathies (SpAs) are characterized by a strong association with the major histocompatibility complex allele HLA-B27. Experimental evidence from humans and transgenic rodents suggests that HLA-B27 is itself involved in the pathogenesis of SpA. Population and peptide-specificity analysis of HLA-B27 suggest it has a pathogenic function related to antigen presentation. Putative roles for infectious agents have been proposed in ReA and suggested in AS. However, the mechanism by which HLA-B27 and bacteria interact to induce arthritis is not clear. Molecular mimicry between bacterial epitopes that cross-react with self-B27 peptides is the most persuasive explanation for the pathogenesis of SpA. The experimental studies reviewed here have greatly increased our knowledge of the structure, function and disease association of HLA-B27.
Mol Med Today 1998 Dec
PMID:The role of HLA-B27 polymorphism and molecular mimicry in spondylarthropathy. 986 24

In the rabbit, expression of immunoglobulin Ckappa1 light chain genes is believed to be under allelic control. Conventionally, four nominal allotypic variants, b4, b5, b6 and b9 have been shown to be co-dominantly expressed at the Ckappa1 gene locus. Analogously, the heavy chain allotypes, VHa1, VHa2 and VHa3, found in the V region, are also believed to be inherited co-dominantly. However, after our earlier discovery of non-allelic or latent allotypes in the serum and on cell surfaces. we subsequently reported that cDNA sequences for latent b5 and b6 were identical to nominal b5 and b6, respectively (Ishaq et al., 1990). The latent b5 cDNAs were from two homozygous b4,b4 rabbits; the latent b6 cDNA was found in a heterozygous b4,b9 rabbit. The cDNA sequences had been obtained from lymph nodes and spleens of rabbits which had been infected with Trypanosoma brucei in order to induce latent allotypes more consistently. In this article, employing spleen DNA from three different T. brucei-infected rabbits, (one, heterozygous b4,b9; two others, homozygous, b4,b4), we initially detected two bands by Southern analysis after Hind III digestion using a 624 base pair Ckappa1 b4 probe derived from a b4,b4 rabbit. However, the probe was non-specific allotypically as it hybridized to b5, b6 and b9 Ckappa1 DNA. Therefore, in order to search for the latent genes, we used allotype-specific oligonucleotides for b5, b6 and b9 to probe DNAs from both normal and T. brucei-infected rabbits by Southern blotting. At the outset, employing a b4 oligonucleotide probe, we detected a single 5.8 Kb segment in two b4,b4 rabbit DNAs after Bg1 II digestion. The findings, using the 624 base pair Ckappa1 b4 probe and the b4 oligomer, agreed with earlier data reported by others. Subsequently, we tested kidney, liver and spleen DNAs from one of these and other rabbits for genomic latent b5, b6 and b9 using these specific oligomeric probes. For each latent allotype, Southern analysis revealed latent-allotype specific DNA segments in the genome. After cosmid cloning and sequencing, latent kappa1, b5, b6 and b9 genes were found to be identical in their coding regions with their nominal counterparts. The genes contained at the 5' end the PyPyXPyAG RNA splice acceptor site found in immunoglobulin and many eukaryotic genes. as well as the termination codon TAG, together with AATAAA and the T-rich sites responsible for cleavage-polyadenylation in the untranslated region downstream from the 3' end. Single cosmid clones representing the b5, b6 and b9 genes were mapped for restriction sites which resulted in identifying putative Jk and enhancer regions. The results thus indicate that latent allotype genes are potentially functional. The data provide evidence that allotypes are not strictly controlled by allelic genes but must be regulated by an hierarchical mechanism which provides for synthesis of allelic allotypes mainly (10-20 mg/ml) together with non-allelic allotypes at lower concentrations (2-20 microg/ml) following activation of the latent genes. These results lay to rest the belief that Ckappa1 latent allotypes are the products of scrambled genes or idiotypic mimicry. Importantly, we now have the possibility of investigating the factors leading to latent allotype gene expression, the Vk and Jk regions associated with the genes, and therefore whether antibody diversity is expanded. We do not know, nor do we imply, that latent allotypes are present in all rabbits. However, since the four conventional Ckappa1 allotypes are present in the genome of several of our tested rabbits, and are presumably functional. we are faced with the probability that rabbit allotypes under certain conditions may in fact behave as isotypes and not allotypes.
Mol Immunol 1998 Oct
PMID:Identification of rabbit immunoglobulin latent Ckappa1 allotype genes alters the concept of allelic inheritance. 988 92

The Aspergillus nidulans transcription factor PacC, which mediates pH regulation, is proteolytically processed to a functional form in response to ambient alkaline pH. The full-length PacC form is unstable in the presence of an operational pH signal transduction pathway, due to processing to the relatively stable short functional form. We have characterized and used an extensive collection of pacC mutations, including a novel class of "neutrality-mimicking" pacC mutations having aspects of both acidity- and alkalinity-mimicking phenotypes, to investigate a number of important features of PacC processing. Analysis of mutant proteins lacking the major translation initiation residue or truncated at various distances from the C terminus showed that PacC processing does not remove N-terminal residues, indicated that processing yields slightly heterogeneous products, and delimited the most upstream processing site to residues approximately 252 to 254. Faithful processing of three mutant proteins having deletions of a region including the predicted processing site(s) and of a fourth having 55 frameshifted residues following residue 238 indicated that specificity determinants reside at sequences or structural features located upstream of residue 235. Thus, the PacC protease cuts a peptide bond(s) remote from these determinants, possibly thereby resembling type I endonucleases. Downstream of the cleavage site, residues 407 to 678 are not essential for processing, but truncation at or before residue 333 largely prevents it. Ambient pH apparently regulates the accessibility of PacC to proteolytic processing. Alkalinity-mimicking mutations L259R, L266F, and L340S favor the protease-accessible conformation, whereas a protein with residues 465 to 540 deleted retains a protease-inaccessible conformation, leading to acidity mimicry. Finally, not only does processing constitute a crucial form of modulation for PacC, but there is evidence for its conservation during fungal evolution. Transgenic expression of a truncated PacC protein, which was processed in a pH-independent manner, showed that appropriate processing can occur in Saccharomyces cerevisiae.
Mol Cell Biol 1999 Feb
PMID:Specificity determinants of proteolytic processing of Aspergillus PacC transcription factor are remote from the processing site, and processing occurs in yeast if pH signalling is bypassed. 989 Oct 72

alpha-Latrotoxin is a presynaptic neurotoxin isolated from the venom of the black widow spider Latrodectus tredecimguttatus. It exerts toxic effects in the vertebrate central nervous system by depolarizing neurons, by increasing [Ca2+]i and by stimulating uncontrolled exocytosis of neurotransmitters from nerve terminals. The actions of alpha-latrotoxin are mediated, in part, by a GTP-binding protein-coupled receptor referred to as CIRL or latrophilin. Exendin-4 is also a venom toxin, and it is derived from the salivary gland of the Gila monster Heloderma suspectum. It acts as an agonist at the receptor for glucagon-like peptide-1(7-36)-amide (GLP-1), thereby stimulating secretion of insulin from pancreatic beta-cells of the islets of Langerhans. Here is reported a surprising structural homology between alpha-latrotoxin and exendin-4 that is also apparent amongst all members of the GLP-1-like family of secretagogic hormones (GLP-1, glucagon, vasoactive intestinal polypeptide, secretin, pituitary adenylyl cyclase activating polypeptide). On the basis of this homology, we report the synthesis and initial characterization of a chimeric peptide (Black Widow GLP-1) that stimulates Ca2+ signaling and insulin secretion in human beta-cells and MIN6 insulinoma cells. It is also reported here that the GTP-binding protein-coupled receptors for alpha-latrotoxin and exendin-4 share highly significant structural similarity in their extracellularly-oriented amino-termini. We propose that molecular mimicry has generated conserved structural motifs in secretagogic toxins and their receptors, thereby explaining the evolution of defense or predatory strategies that are shared in common amongst distantly related species including spiders, lizards, and snakes. Evidently, the toxic effects of alpha-latrotoxin and exendin-4 are explained by their ability to interact with GTP-binding protein-coupled receptors that normally mediate the actions of endogenous hormones or neuropeptides.
Comp Biochem Physiol B Biochem Mol Biol 1998 Oct
PMID:Black widow spider alpha-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. 997 93

Uracil-DNA glycosylase (UDG), which is a critical enzyme in DNA base-excision repair that recognizes and removes uracil from DNA, is specifically and irreversably inhibited by the thermostable uracil-DNA glycosylase inhibitor protein (Ugi). A paradox for the highly specific Ugi inhibition of UDG is how Ugi can successfully mimic DNA backbone interactions for UDG without resulting in significant cross-reactivity with numerous other enzymes that possess DNA backbone binding affinity. High-resolution X-ray crystal structures of Ugi both free and in complex with wild-type and the functionally defective His187Asp mutant Escherichia coli UDGs reveal the detailed molecular basis for duplex DNA backbone mimicry by Ugi. The overall shape and charge distribution of Ugi most closely resembles a midpoint in a trajectory between B-form DNA and the kinked DNA observed in UDG:DNA product complexes. Thus, Ugi targets the mechanism of uracil flipping by UDG and appears to be a transition-state mimic for UDG-flipping of uracil nucleotides from DNA. Essentially all the exquisite shape, electrostatic and hydrophobic complementarity for the high-affinity UDG-Ugi interaction is pre-existing, except for a key flip of the Ugi Gln19 carbonyl group and Glu20 side-chain, which is triggered by the formation of the complex. Conformational changes between unbound Ugi and Ugi complexed with UDG involve the beta-zipper structural motif, which we have named for the reversible pairing observed between intramolecular beta-strands. A similar beta-zipper is observed in the conversion between the open and closed forms of UDG. The combination of extremely high levels of pre-existing structural complementarity to DNA binding features specific to UDG with key local conformational changes in Ugi resolves the UDG-Ugi paradox and suggests a potentially general structural solution to the formation of very high affinity DNA enzyme-inhibitor complexes that avoid cross- reactivity.
J Mol Biol 1999 Mar 26
PMID:Protein mimicry of DNA from crystal structures of the uracil-DNA glycosylase inhibitor protein and its complex with Escherichia coli uracil-DNA glycosylase. 1008 Aug 96


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