Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Insect defensins are cationic, inducible antibacterial peptides. Four full-length cDNAs encoding defensin A from the mosquito Aedes aegypti were cloned using polymerase chain reaction (PCR) and sequenced. All four cDNAs are 473 base pairs long, bearing an open reading frame of 98 amino acids with a few substitutions in the signal peptide domain. The deduced amino acid sequence of Aedes aegypti defensin (AaDef) contains a signal peptide sequence of 18 amino acids followed by a 40-amino acid putative propeptide domain and a 40-amino acid mature peptide domain. The mature peptide, with a predicted M(r) of 4148, shows 80% identity and 93% similarity to Phormia defensin A, and is identical to the peptide sequencing data for mosquito defensin A of Lowenberger et al. (1995) and B of Chalk et al. (1995). There are three potential phosphorylation sites but no glycosylation sites detected in AaDef. Three putative disulfide linkages between cysteines, characteristic of insect defensins, are conserved in AaDef. Aedes aegypti defensin mRNA is produced in response to a bacterial challenge; it is dramatically enhanced 6 h after bacterial injection, continues to increase through 24 h, and is maintained at high levels until at least 30 h post-bacterial injection.
Insect Biochem Mol Biol 1996 Apr
PMID:Cloning and characterization of cDNAs encoding the antibacterial peptide, defensin A, from the mosquito, Aedes aegypti. 881 87

The mammalian defensin molecule is a short, highly cationic peptide cytotoxic to both microbial and mammalian cells which is cleaved from a precursor including a signal peptide and a highly anionic propiece. A phylogenetic analysis of 28 complete sequences from five mammalian species (mouse, rat, guinea pig, rabbit, and human) showed species-specific clusters of sequences, indicating that the genes duplicated after divergence of these species. Comparison of rates of synonymous and nonsynonymous nucleotide substitution suggested that gene duplication has often been followed by a period in which diversification of the mature defensins at the amino acid level has been selectively favored. In some comparisons, it appeared that amino acid differences in this region have appeared in a nonrandom fashion so as to change the pattern of residue charges. Because it has been hypothesized that the negative charge in the propiece serves to balance the positive charge in the mature defensin and thus to prevent cytotoxicity prior to cleavage, we used a maximum likelihood method of reconstructing ancestral states in order to test whether this balance has been maintained over evolutionary time in spite of rapid diversification of the mature defensin at the amino acid level. Reconstructed ancestral sequences always maintained a charge balance between mature defensin and propiece, and changes in the net positive charge of the mature defensin were balanced by corresponding changes in the propiece. The results support the hypothesis that, in the evolution of these proteins, amino acid changes have occurred in a coordinated fashion so as to preserve an adaptive phenotype.
J Mol Evol 1997 Jun
PMID:Coordinated amino acid changes in the evolution of mammalian defensins. 916 60

Insect immune proteins, defensins, are inducible anti-Gram-positive bacterial peptides. We report here the identification of two defensin genes from the mosquito, Aedes aegypti, which encode a large 541 bp transcript (AaDef Ala) and a small 473 bp transcript (AaDef Asm). The cDNA corresponding to AaDef Ala was cloned, sequenced, and compared with the previously reported AaDef Asm cDNA. The AaDef Ala gene was isolated through genomic library screening and characterized. It putative regulatory region contains a 64 bp intron, a TATA box and a putative arthropod initiator. Two 150 bp long direct and several palindromic repeats are present in this sequence. Similar to other insect immune peptide genes, the AaDef Ala gene contains numerous putative regulatory motifs with impressive similarity to elements of vertebrate acute phase response protein genes.
Insect Biochem Mol Biol 1997 May
PMID:Molecular characterization of a defensin gene from the mosquito, Aedes aegypti. 921 62

We present here the isolation and characterization of four antimicrobial peptides produced by a European bumblebee Bombus pascuorum. A 51-residue insect defensin was characterized which, like the Apis mellifera defensins, had a highly conserved 12-residue extension to its C-terminal compared to defensins from other insects. Monoisotopic mass analysis of the C-terminal of B. pascuorum defensin confirmed that this molecule was C-terminally amidated. This defensin showed strong anti-Gram-positive activity and some anti-fungal activity; also, in contrast to other insect defensins, it showed anti-Gram-negative activity. A 17-residue apidaecin was characterized, showing anti-Gram-negative activity, and differing by a single amino acid substitution from the A. mellifera apidaecin. A 39-residue abaecin was isolated, the largest proline-rich antimicrobial peptide characterized to date, which showed activity against both Gram-negative and Gram-positive bacteria. Finally, we isolated an N-terminally blocked molecule, with a molecular mass of 10,122 Da, which showed activity against Gram-negative bacteria only. These characteristics are reminiscent of hymenoptaecin from the honeybee A. mellifera, but a definitive characterization of this molecule awaits further work. No evidence of lysozyme activity was found in the haemolymph of challenged or naive B. pascuorum.
Insect Biochem Mol Biol 1997 May
PMID:Novel antibacterial peptides isolated from a European bumblebee, Bombus pascuorum (Hymenoptera, Apoidea). 921 67

AML-1B is a hematopoietic transcription factor that is functionally inactivated by multiple chromosomal translocations in human acute myeloblastic and B-cell lymphocytic leukemias. The t(8;21)(q22;q22) translocation replaces the C terminus, including the transactivation domain of AML-1B, with ETO, a nuclear protein of unknown function. We previously showed that AML-1-ETO is a dominant inhibitor of AML-1B-dependent transcriptional activation. Here we demonstrate that AML-1-ETO also inhibits C/EBP-alpha-dependent activation of the myeloid cell-specific, rat defensin NP-3 promoter. AML-1B bound the core enhancer motifs present in the NP-3 promoter and activated transcription approximately sixfold. Similarly, C/EBP-alpha bound NP-3 promoter sequences and activated transcription approximately sixfold. Coexpression of C/EBP-alpha with AML-1B or its family members, AML-2 and murine AML-3, synergistically activated the NP-3 promoter up to 60-fold. The t(8;21) product, AML-1-ETO, repressed AML-1B-dependent activation of NP-3 and completely inhibited C/EBP-alpha-dependent activity as well as the synergistic activation. In contrast, the inv(16) product, which indirectly targets AML family members by fusing their heterodimeric DNA binding partner, CBF-beta, to the myosin heavy chain, inhibited AML-1B but not C/EBP-alpha activation or the synergistic activation. AML-1-ETO and C/EBP-alpha were coimmunoprecipitated and thus physically interact in vivo. Deletion mutants demonstrated that the C terminus of ETO was required for AML-1-ETO-mediated repression of the synergistic activation but not for association with C/EBP-alpha. Finally, overexpression of AML-1-ETO in myeloid progenitor cells prevented granulocyte colony-stimulating factor-induced differentiation. Thus, AML-1-ETO may contribute to leukemogenesis by specifically inhibiting C/EBP-alpha- and AML-1B-dependent activation of myeloid promoters and blocking differentiation.
Mol Cell Biol 1998 Jan
PMID:The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. 941 79

The transmembrane glycoprotein gp41 of HIV-1 contains a C1q binding domain (HIVenv 583-610) and activates the human complement system through the classical pathway. Based on structural and functional similarities between human defensins (human neutrophil peptide, HNP 1-3) and synthetic peptides representing the env 583-610 region of HIV-1, we found it interesting to investigate the C1q binding and complement activating ability of human defensins. Human defensins were purified and characterized by size exclusion chromatography, ultrafiltration, gel electrophoresis and HPLC. The complement activating ability of the purified peptides was assessed in a solid-phase immunoassay. Defensins, fixed to an ELISA plate, were able to bind the C1q subcomponent of the first complement component (C1), triggering the classical pathway of complement activation which led to C4b binding to the plate. Reduction and subsequent alkylation of disulfide bridges of defensins greatly decreased the C1q binding ability but complement activation (C4b binding) remained high. Further acetylation of the reduced defensin peptide resulted in a molecule which bound very little or no C1q but still activated the complement cascade. These phenomena indicate that defensins interact with the complement system via C1q-dependent and C1q-independent mechanisms, and extend the number of functional similarities between defensins and gp41 of HIV-1 to include C1q binding and complement activation.
Mol Immunol 1997 Aug
PMID:Defensins purified from human granulocytes bind C1q and activate the classical complement pathway like the transmembrane glycoprotein gp41 of HIV-1. 944 79

Raphanus sativus Antifungal Protein 1 (Rs-AFP1) is a 51 amino acid residue plant defensin isolated from radish (Raphanus sativus L.) seeds. The three-dimensional structure in aqueous solution has been determined from two-dimensional 1H NMR data recorded at 500 MHz using the DIANA/REDAC calculation protocols. Experimental constraints consisted of 787 interproton distances extracted from NOE cross-peaks, 89 torsional constraints from 106 vicinal interproton coupling constants and 32 stereospecific assignments of prochiral protons. Further refinement by simulated annealing resulted in a set of 20 structures having pairwise root-mean-square differences of 1.35(+/- 0.35) A over the backbone heavy atoms and 2.11(+/- 0.46) A over all heavy atoms. The molecule adopts a compact globular fold comprising an alpha-helix from Asn18 till Leu28 and a triple-stranded beta-sheet (beta 1 = Lys2-Arg6, beta 2 = His33-Tyr38 and beta 3 = His43-Pro50). The central strand of this beta-sheet is connected by two disulfide bridges (Cys21-Cys45 and Cys25-Cys47) to the alpha-helix. The connection between beta-strand 2 and 3 is formed by a type VIa beta-turn. Even the loop (Pro7 to Asn17) between beta-strand 1 and the alpha-helix is relatively well defined. The structure of Raphanus sativus Antifungal Protein 1 features all the characteristics of the "cysteine stabilized alpha beta motif". A comparison of the complete structure and of the regions important for interaction with the fungal receptor according to a mutational study, is made with the structure of gamma-thionin, a plant defensin that has no antifungal activity. It is concluded that this interaction is both electrostatic and specific, and some possible scenarios for the mode of action are given.
J Mol Biol 1998 May 29
PMID:Determination of the three-dimensional solution structure of Raphanus sativus antifungal protein 1 by 1H NMR. 963 15

We have characterized two members of a gene family encoding defensin-type proteins, j1-1 and j1-2. The structures of these homologous genes are highly similar. Both genes contain an intervening sequence at the same position. Sequence analysis of the intron within the j1-2 gene revealed the existence of an additional exon (exon 2ji) which also encodes a defensin-type protein. It is very likely that this exon was derived by genomic shuffling from a gene, jx, belonging to another subfamily which remains to be characterized. Only transcripts resulting from the splicing of exons 1j2 and 2ji can be detected, indicating that the inserted exon has functionally replaced the original, leaving the latter as a partial pseudogene. This rearrangement did not alter the tissue specificity of expression of the gene j1-2. The corresponding transcripts, present at the stage of fruit set, accumulate progressively during the process of development. In contrast, gene j1-1 is expressed only at the later stages of ripening. Estimates of transcription rates show that in green fruits expression is mainly regulated at a post-transcriptional level, while transcriptional regulation is prominent during ripening.
Mol Gen Genet 1998 Sep
PMID:Alteration of the expression of a plant defensin gene by exon shuffling in bell pepper (Capsicum annuum L.). 979 May 81

Structural superimposition is an important procedure to analyse the relationships between proteins. A new approach and program, KNOT-MATCH, has been developed for automated structural superimposition of proteins by means of their disulphide bridge topology. As a result of the superimposition, regular secondary structures, loops and clusters of residues become correctly aligned. This fact allows us to find out important structural overlaps of residues, sometimes with functional significance, not only among proteins belonging to the same family but also between apparently non-related proteins. Different disulphide-rich protein families, such as EGF-like, defensin-like and plant protease inhibitors, have been self or cross analysed with this approach. Some amino acids that have been experimentally determined to be structural and/or functional key residues for these proteins are conserved in the three-dimensional space after superimposition by KNOT-MATCH. The program can be very useful for finding relationships among proteins that would be hidden to the current alignment methods based on sequence and on main-chain topology.
J Mol Biol 1998 Dec 04
PMID:Protein similarities beyond disulphide bridge topology. 982 96

The plant defensin PDF1.2 has previously been shown to accumulate systemically via a salicylic acid-independent pathway in leaves of Arabidopsis upon challenge by fungal pathogens. To further investigate the signalling and transcriptional processes underlying plant defensin induction, a DNA fragment containing 1184 bp and 1232 bp upstream of the transcriptional and translational start sites, respectively, was cloned by inverse PCR. To test for promoter activity this DNA fragment was linked to the beta-glucuronidase (GUS)-encoding region of the UidA gene as a translational fusion and introduced into Arabidopsis ecotype C-24. Challenge of the transgenic plants with the fungal pathogens Alternaria brassicicola and Botrytis cinerea resulted in both local and systemic induction of the reporter gene. Wounding of the transgenic plants had no effect on GUS activity. Treatment of the transgenic plants with either jasmonates or the active oxygen generating compound paraquat strongly induced the reporter gene. In contrast, neither salicylate nor its functional analogues 2,6-dichloroisonicotinic acid and 1,2,3-benzothiodiazole-7-carbothioic acid S-methyl ester resulted in reporter gene induction. These results are consistent with the existence of a salicylic acid-independent signalling pathway, possibly involving jasmonates as regulators, that is triggered by pathogen challenge but not by wounding. The transgenic plants containing the PDF1.2-based promoter-reporter construct will provide useful tools for future genetic dissection of this novel systemic signalling pathway.
Plant Mol Biol 1998 Dec
PMID:The promoter of the plant defensin gene PDF1.2 from Arabidopsis is systemically activated by fungal pathogens and responds to methyl jasmonate but not to salicylic acid. 986 13


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