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PubMed1995

Hairpin loop mutations of chicken cystatin have different effects on the inhibition of cathepsin B, cathepsin L and papain.

Five recombinant hairpin loop variants of chicken cystatin (delta V55, delta V55-S56, delta P103-L105, delta I102-Q107, loop2-KD2) were constructed by cassette mutagenesis, expressed in E. coli, purified to homogeneity, characterized by protein-chemical means and by their inhibitory properties. The variant forms, modified in two of the three postulated cysteine proteinase binding regions, were inhibitorily active. However, the equilibrium dissociation constants of the complexes between papain as well as human cathepsin B or L and the cystatin variants show a weaker affinity for all three enzymes compared with recombinant chicken cystatin. These results prove the contribution of both hairpin loops to complex formation with the three enzymes. Furthermore, the kinetic constants indicate discrete differences in the molecular mechanism of interaction between chicken cystatin and papain, cathepsin B, and cathepsin L. Inhibition of cathepsin L was much less affected than inhibition of papain or cathepsin B by the modifications achieved in the five variants. Remarkably, at high enzyme concentration (above 0.5 nM) inhibition of papain by these variants was 'temporary', that means, active papain was released from the enzyme-inhibitor complex within minutes to hours (compare [1]).

Amino Acid Sequence↗

PubMed1993

Binding constant determination studies utilizing recombinant delta CREB protein.

In this study, we report the binding constants (Kd) of the cAMP-responsive element binding protein (delta-CREB) for various cAMP-response element (CRE) motifs. We utilized purified recombinant delta CREB protein in binding reactions with natural CRE motifs found in the promoter of two neuropeptide hormone genes and with several variant CRE motifs. The Kd of delta CREB for the perfectly palindromic CRE, TGACG-TCA, found within the somatostatin promoter is estimated to be 5.0 x 10(-9) M. The Kd of delta CREB for the variant CRE motif TG_CGTCA found within the enkephalin promoter is calculated to be in the 3 x 10(-8) M. These studies provide an in vitro quantitative assessment of the binding affinity of delta CREB for various CRE motifs.

Amino Acid Sequence↗

PubMed2005

Hepatitis C virus NS3 protein interacts with ELKS-{delta} and ELKS-{alpha}, members of a novel protein family involved in intracellular transport and secretory pathways.

The NS3 protein of hepatitis C virus (HCV) has a serine protease activity in its N-terminal region, which plays a crucial role in virus replication. This region has also been reported to interact not only with its viral cofactor NS4A, but also with a number of host-cell proteins, which suggests a multifunctional feature of NS3. By means of yeast two-hybrid screening using an N-terminal region of NS3 as bait, a human cDNA encoding a region of ELKS-delta, a member of a novel family of proteins involved in intracellular transport and secretory pathways, was molecularly cloned. Using co-immunoprecipitation, GST pull-down and confocal and immunoelectron microscopic analyses, it was shown that full-length NS3 interacted physically with full-length ELKS-delta and its splice variant, ELKS-alpha, both in the absence and presence of NS4A, in cultured human cells, including Huh-7 cells harbouring an HCV subgenomic RNA replicon. The degree of binding to ELKS-delta varied with different sequences of the N-terminal 180 residues of NS3. Interestingly, NS3, either full-length or N-terminal fragments, enhanced secretion of secreted alkaline phosphatase (SEAP) from the cells, and the increase in SEAP secretion correlated well with the degree of binding between NS3 and ELKS-delta. Taken together, these results suggest the possibility that NS3 plays a role in modulating host-cell functions such as intracellular transport and secretion through its binding to ELKS-delta and ELKS-alpha, which may facilitate the virus life cycle and/or mediate the pathogenesis of HCV.

Adaptor Proteins, Signal Transducing↗

PubMed2000

cDNA cloning of the Cry1Aa receptor variants from Bombyx mori and their expression in mammalian cells.

We cloned cDNA of three variants of BtR175, a putative Bombyx mori receptor for Bacillus thuringiensis Cry1Aa delta-endotoxin by PCR. These variants were likely to be allelic to BtR175. cDNA of BtR175b, the most distant variant from BtR175, was introduced into mammalian cells. BtR175b protein was expressed in the plasma membrane of the cells and showed binding activity to Cry1Aa.

Alternative Splicing↗

PubMed1994

G6PD Ferrara I has the same two mutations as G6PD A(-) but a distinct biochemical phenotype.

The cloning and sequencing of the normal glucose-6-phosphate dehydrogenase (G6PD) gene has led to the study of the molecular defects that determine enzymatic variants. In this paper, we describe the mutations responsible for the Ferrara I variant in an Italian man with a family history of favism, from the Po delta. Nucleotide sequencing of this variant showed a G-->A mutation at nucleotide 202 in exon IV causing a Val-->Met amino acid exchange, and a second A-->G mutation at nucleotide 376 in exon V causing an Asn-->Asp amino acid substitution. Although on the basis of its biochemical properties this variant was classified as G6PD Ferrara I, it has the same two mutations as G6PD A(-), which is common in American and African blacks, and as the sporadic Italian G6PD Matera. The mutation at nucleotide 202 was confirmed by NlaIII digestion of a polymerase chain reaction amplified DNA fragment spanning 109 bp of exon IV. The 109-bp mutated amplified sequence is not distinguishable from the normal sequence in single strand conformation polymorphism analysis.

Cloning, Molecular↗

PubMed1992

Ontogeny of GABAA/benzodiazepine receptor subunit mRNAs in the murine inferior olive: transient appearance of beta 3 subunit mRNA and [3H]muscimol binding sites.

The GABAA/benzodiazepine receptor consists of at least four subunits, alpha, beta, gamma and delta, each comprised of several variants. The developmental expression of the alpha 1, beta 1-3, gamma 2 and delta subunits was studied in the murine inferior olivary nucleus by in situ hybridization with antisense cRNA probes. The postnatal appearance and distribution of [3H]flunitrazepam and [3H]muscimol binding sites, alpha and beta subunit-specific ligands respectively, were also studied autoradiographically. The beta 3 subunit was transiently expressed in each of the subnuclei of the inferior olive: The signal was strong at birth, increased throughout postnatal week 1 and rapidly declined thereafter to low adult levels. A similar pattern of labeling was observed with [3H]muscimol. Detectable levels of alpha 1 subunit mRNA hybridization signal and [3H]flunitrazepam binding sites were also present in the inferior olive at birth, decreasing thereafter. Low to moderate levels of beta 1, beta 2, and gamma 2 subunit mRNAs were present in olivary neurons throughout postnatal development, while delta mRNAs were largely absent. It has been reported previously that, during the 2nd postnatal week, the ratio of climbing fiber terminals to Purkinje cells is reduced from 3:1, as observed in neonates, to the 1:1 relationship observed in the adult cerebellar cortex. Our results raise the possibility that the subunit composition of the GABAA/benzodiazepine receptor in inferior olivary neurons undergoes changes during development, and that this process may be related to the elimination of multiple climbing fiber innervation of cerebellar Purkinje cells.

Animals↗

PubMed1997

Molecular heterogeneity of the cDNA encoding a 74-kDa regulatory subunit (B" or delta) of human protein phosphatase 2A.

Two cDNAs for possible splicing variants of a 74-kDa regulatory subunit (B" or delta) of human protein phosphatase 2A, were isolated. These variants were identified from human cerebral cortex by library screening and PCR, and designated delta1 and delta3 isoforms, while the previously reported isoform [Tanabe et al. (1996) FEBS Lett. 379, 107-1111 was designated delta2. Compared with the delta2 isoform, the delta1 isoform contained a 32-residue insertion beginning at residue 84, and consisted of 602 amino acids in all. The delta3 isoform lacked a 74-residue sequence corresponding to residues 1083 of the delta2 isoform, and consisted of 496 amino acids. Using isoform-specific antipeptide antisera, the 74-kDa subunit (B" or delta) originally purified from human erythrocytes was identified as the delta1 isoform.

Alternative Splicing↗

PubMed1988

A family study of multiple mutations of alpha and delta glycophorins (glycophorins A and B).

Glycophorins alpha and delta are the carriers of the antigens of the MNSs blood system; this report documents the presence of three glycophorin mutations in two individuals of a 16 member family. Erythrocytes were examined by serology, sodium dodecyl sulfate electrophoresis, and immunoblotting. The inheritance pattern and immunoblot profile revealed: (1) A variant Dantu glycophorin showed properties consistent with a delta-alpha glycophorin hybrid structure, previously noted in other individuals. The gene responsible for the Dantu glycophorin in this family is linked to a gene coding for an M-specific alpha glycophorin. (2) Another variant glycophorin, Mi-III glycophorin, was first revealed by immunoblotting and subsequently confirmed by erythrocyte antigen typing. This autosomal dominant trait is associated with N blood group activity and the inheritance pattern indicates that it could be a variant of delta glycophorin. (3) In the individuals with both Dantu and Mi-III glycophorins a delta glycophorin deficiency was observed suggesting that a deletion or alteration of delta gene may exist cis to the Dantu gene. Our findings that document clustering of multiple mutations in MNSs gene loci in the propositus family are very unusual as such variants are relatively rare.

Female↗

PubMed1998

Structure-activity study of the lantibiotic mutacin II from Streptococcus mutans T8 by a gene replacement strategy.

Mutacin II, elaborated by group II Streptococcus mutans, is a ribosomally synthesized and posttranslationally modified polypeptide antibiotic containing unusual thioether and didehydro amino acids. To ascertain the role of specific amino acid residues in mutacin II antimicrobial activity, we developed a streptococcal expression system that facilitates the replacement of the mutA gene with a single copy of a mutated variant gene. As a result, variants of mutacin II can be designed and expressed. The system was tested by constructing the following mutant peptides: delta N1, V7A, P9A, T10A, T10S, C15A, C26A, and C27A. All of these mutacin II variants except delta N1 and T10A, which were not secreted, were isolated, and their identities were verified by mass spectrometry. Variants P9A, C15A, C26A, and C27A failed to exert antimicrobial activity. Because the P9A and T10A variants comprise the "hinge" region of mutacin II, these observations suggest that in addition to the thioether and didehydro amino acids, the hinge region is essential for biological activity and biosynthesis or export of the peptide. Tandem mass spectrometry of the N-terminal part of the wild-type molecule and its C15A variant confirmed that the threonine at position 10 is dehydrated and present as a didehydrobutyrine residue. This analysis of the active T10S variant further suggested that a didehydro amino acid at this position is specific for antimicrobial activity and that the biosynthetic machinery does not discriminate between threonine and serine. In contrast, the lack of production of mutacin variants with alanine substituted for threonine at position 10, as well as the deletion of asparagine at the N terminus (delta N1), indicates that specific residues in the propeptide may be crucial for certain steps in the biosynthetic pathway of this lantibiotic.

Amino Acid Sequence↗

PubMed1996

Molecular studies on bromovirus capsid protein. I. Characterization of cell-to-cell movement-defective RNA3 variants of brome mosaic virus.

To evaluate the extent to which brome mosaic virus (BMV) coat protein (CP) gene is involved in the process of cell-to-cell movement. Chenopodium quinoa plants were coinoculated with BMV wild-type RNAs 1 and 2 and a RNA3 variant containing either the beta-glucuronidase (GUS) gene in place of CP (B3/CP-GUS), to be subjected to GUS analysis, or a deletion in the CP gene to be analyzed by fluorescence in situ hybridization (FISH). Irrespective of time postinoculation, GUS expressed from the subgenomic mRNA of B3/CP-GUS was restricted to initially infected, single epidermal cells. The defective cell-to-cell movement exhibited by B3/CP-GUS was not complemented in trans when transcripts of B3 delta MP, a RNA3 variant capable of synthesizing functional wt CP but not movement protein (MP), were added to the inoculum. Application of FISH, a technique versatile in discriminating subliminal infections from efficient cell-to-cell spread in nonpermissive and permissive hosts, respectively, to leaves inoculated with BMV RNA3 variants defective in CP synthesis, confirmed that the resulting infections were subliminal. These data provide direct evidence for the requirement of an encapsidation-competent CP to be expressed in conjunction with a functional MP for efficient cell-to-cell spread of BMV.

Bromovirus↗

PubMed1996

Modulation of cytokine expression by CD4+ T cells during coxsackievirus B3 infections of BALB/c mice initiated by cells expressing the gamma delta + T-cell receptor.

Two variants of coxsackievirus B3 have been used to investigate the pathogenesis of myocarditis in BALB/c mice. H3 virus induces moderate myocarditis and H310A1 virus induces minimal myocarditis, although both viruses infect and replicate in the heart. Cells expressing the gamma delta+ T-cell receptor composed 5 to 13% of the lymphocytes infiltrating the hearts of H3 virus-infected mice and belonged to either the CD4- CD8+ gamma delta+- or CD4- CD8- gamma delta+-cell population. Giving 5,000 gamma delta+ cells isolated from the hearts of H3 virus-infected mice to H310A1 virus-infected recipients restored myocarditis susceptibility in the recipient animals and shifted the pattern of cytokine production in the virus-immune CD4+-cell population from being predominantly interleukin-4 producing to being predominantly gamma interferon producing in the H310A1 virus-infected mice. Apoptosis was evident in the infiltrating lymphocyte population in the myocardia of H3 virus-infected mice by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay and in splenic lymphocytes by DNA fragmentation in agarose gel electrophoresis and was confined to the CD4+ population. No apoptosis was observed in H310A1 virus-infected mice, but apoptosis was induced subsequent to gamma delta +-T-cell transfer. These results are consistent with the hypothesis that gamma delta+ T cells may help modulate cytokine responses during virus infections in vivo and that apoptosis might be involved in this modulation.

Animals↗

PubMed2025

Cycle threshold values and SARS-CoV-2 variant associations with breakthrough infections: a retrospective study in Accra, Ghana.

BACKGROUND: Breakthrough infections are defined as SARS-CoV-2 infections occurring ≥ 14 days after completing the primary COVID-19 vaccination series and remain a public health challenge, particularly in regions where immune-evasive variants are circulating. However, data on their virological and clinical profiles in low-resource settings are limited. METHODS: This retrospective study was conducted from July to December 2022 in Accra, Ghana, among individuals testing positive for SARS-CoV-2. Real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) was performed using the Allplex™ 2019-nCoV Assay. Cycle threshold (Ct) values for the nucleocapsid (N), RNA-dependent RNA polymerase (RdRP), and envelope (E) genes, categorised as < 25, 25–30, or > 30. Variant identification targeted Alpha, Delta, and Omicron mutations using mutation-specific RT-PCR. Logistic regression was used to assess associations between vaccination status and demographic, clinical, and virological factors. RESULTS: Of the 268 samples analysed, 81 tested positive; 43.20% [n = 35] were vaccinated individuals. Median Ct-values for the N [27.13, IQR: 21.59–31.96] and E [24.57, IQR: 19.43–29.43] genes were significantly higher among vaccinated cases, indicating lower viral loads. Breakthrough infections were strongly associated with the Omicron variant [aOR = 4.38, p = 0.034]. Diarrhoea [aOR = 9.67, p = 0.022], sore throat [aOR = 8.99, p = 0.038], headache [aOR = 10.156, p = 0.039] and chills [aOR = 3.316, p = 0.046] were mostly associated with breakthrough infections. Ct-values of 25–30 [aOR = 11.33, p = 0.012] and > 30 [aOR = 4.01, p = 0.047] were significantly associated with breakthrough infection compared to Ct < 25 in breakthrough infections. CONCLUSION: Vaccinated individuals with SARS-CoV-2 infection had lower viral loads and were more likely to be infected with the Omicron variant. These findings reinforce the role of vaccination in reducing viral load and support the adoption of practical surveillance strategies, such as Ct value-based surveillance and variant screening in low middle-income countries facing similar constraints in genomic capacity and vaccine deployment.

Humans↗

PubMed1991

The complete amino-acid sequence of the heavy chain of the human myeloma protein WIE, an immunoglobulin D.

The human myeloma protein WIE is a lambda-type immunoglobulin D; the amino-acid sequence of its Fc part and aminoethylated heavy chain was completely determined. The VH-part (subgroup III) begins N-terminally with 5-oxoproline, and it contains a long, unique CDR3 region. Since the constant part differs from known delta chains by one amino-acid substitution in the hinge region, IgD WIE probably represents an allotypic variant. As in other protein delta chains, O-glycosylations are confined to the hinge region. Furthermore, the ratios of N-glycosylations at the three positions are identical in IgD WAH [Takahashi, N. et al. (1984) J. Chromatogr. 317, 11-26.] and IgD WIE (100%, 50%, 100%). From the most conserved constant domain, C delta 3, a three-dimensional model was constructed to clarify the role of its delta-specific substitutions and glycosylation.

Amino Acid Sequence↗

PubMed2000

Differential expression and subcellular localization of murine BRCA1 and BRCA1-delta 11 isoforms in murine and human cell lines.

BRCA1 mutations are involved in breast and ovarian cancer predisposition in humans. The biological functions of the murine BRCA1 gene have been extensively studied but little is known about murine BRCA1 proteins. To better characterize these proteins, we have cloned the full-length murine BRCA1 cDNA and a splice variant deleted of exon 11, BRCA1-delta 11, by RT-PCR method. Three polyclonal antibodies raised against various parts of murine BRCA1 were used in our study: D16, M20 and 5MO, which were generated in our laboratory. This allowed us to analyze the expression and subcellular localization of both isoforms in murine and human cell lines by immunoblotting, immunoprecipitation, cell fractionation and immunofluorescence. Endogenous BRCA1 was detected in murine cell lines but not splice variant BRCA1-delta 11, whereas both ectopically expressed murine isoforms were detected in transfected human Bosc 23 cells. Subcellular fractionation and immunofluorescence results showed that the BRCA1 protein was mainly located in the nucleus, whereas BRCA1-delta 11 was preferentially cytoplasmic. The conservation of exon 11 splicing and the differential subcellular localization of BRCA1 and BRCA1-delta 11 in human and mouse suggest that these proteins could play distinct roles and that they could differentially act in the pathological mechanisms leading to the development of breast and ovarian cancer. The characterization of the murine BRCA1 proteins and antibodies will be useful to further study BRCA1 functions in murine models.

3T3 Cells↗

PubMed2002

Association of SH2-B to phosphorylated tyrosine residues in the activation loop of TrkB.

Neurotrophins are essential for the survival and differentiation of neurons in the central and peripheral nervous systems. The binding of neurotrophins to their Trk receptors induces autophosphorylation of tyrosine residues and activation of several signaling components. However, the downstream signaling cascades remain to be fully elucidated. Here we describe molecular cloning of human SH2-B alpha, PH and SH2-domain-containing adaptor protein, as a TrkB binding protein, and how SH2-B alpha associate with the cytoplasmic domain of TrkB at phosphorylated tyrosine residues in the kinase activation loop. There was no distinct inhibitory or inducing effect on kinase activity detected by either a full-length or an SH2 domain of SH2-B alpha in vitro, even though the regulation mechanism of the activation loop on tyrosine kinase activity has been described. In addition to SH2-B alpha, the expression of three SH2-B alternative splice variants, SH2-B beta, gamma and delta, was detected in human cell lines. These splicing variants have unique carboxyl-terminal amino acid sequences due to insertion sequences as well as reading frameshifts.

Amino Acid Sequence↗

PubMed1994

Biological activities and secondary structures of variant forms of human salivary cystatin SN produced in Escherichia coli.

Using an Escherichia coli expression system, pGEX-2T, that expresses foreign sequences as fusion proteins with a glutathione S-transferase (GST) carrier, we have produced several recombinant human salivary cystatin SN (reCsnSN) variants. These include a N-terminal-truncated form (aa 17-121), a C-terminal-truncated form (aa 1-102) and two deletion mutants (delta 12-16 and delta 56-60). A large amount of the insoluble fusion protein (approx. 15 mg/l) was produced in each case. These were solubilized with urea and refolded by dialysis. The GST carrier was then cleaved with thrombin and the reCsn variants (except delta 56-60) were purified by anion-exchange chromatography. The CysP inhibitory activities against papain, and bovine and human cathepsin B, and secondary structures of the reCsnSN variants were determined and compared to natural salivary CsnSN. The full-length reCsnSN, the N-truncated and the delta 12-16 variants inhibited the CysP activity of papain and displayed circular dichroism (CD) spectra similar to that of natural CsnSN. On the other hand, the delta 56-60 mutant and the C-truncated variant exhibited very little inhibitory activity towards papain. The CD spectrum of the C-truncated variant indicated a change in the secondary structure (e.g., a decrease in beta-sheet and an increase of an alpha-helical content). Neither, the natural nor the full-length reCsnSN or the delta 12-16 mutant exhibited any inhibitory activity towards bovine and human cathepsin B.

Amino Acid Sequence↗

PubMedDate not supplied

Generation of a variant of human interleukin-4 by alternative splicing.

A second species of interleukin-4 (IL-4) mRNA was identified using both a reverse transcription-polymerase chain reaction and an RNase protection assay. This novel IL-4 mRNA was 48 base pairs smaller than IL-4 mRNA, which is the size of IL-4 exon 2. Sequence data of cloned cDNA demonstrated that this variant contained IL-4 exons 1,3 and 4, with exon 1 spliced directly to exon 3 in an open reading frame. The entire protein encoding region of this variant, named IL-4 delta 2, was identical to IL-4 except for the omission of exon 2. IL-4 delta 2 mRNA was detected in all human peripheral blood mononuclear cells tested and in purified CD3+ T cells. Amounts of both IL-4 and IL-4 delta 2 mRNAs increased upon T cell activation, although IL-4 mRNA increased to a greater extent than IL-4 delta 2 mRNA did. Human IL-3, IL-5, IL-13, and granulocyte macrophage-colony stimulating factor did not use alternative splicing to delete exon 2. We speculate that IL-4 delta 2 may regulate IL-4 function.

Alternative Splicing↗

PubMed2001

Prostaglandin D(2) receptor-mediated desensitization of the alpha isoform of the human thromboxane A(2) receptor.

Thromboxane (TX) A(2) and prostaglandin (PG) D(2) mediate opposing actions in platelets and in vascular and non-vascular smooth muscle. Here, we investigated the effects of stimulation of the PGD(2) receptor (DP) on signaling by the TXA(2) receptor (TP) expressed in human platelets and in human embryonic kidney (HEK) 293 cells over-expressing the individual TP alpha and TP beta isoforms. In platelets, the selective DP agonist BW245C abolished TP-mediated mobilization of intracellular calcium ([Ca(2+)](i)) and inhibited platelet aggregation in response to the TXA(2) mimetic U46619. DP-mediated desensitization of TP signaling in platelets was prevented by pretreatment with the cAMP-dependent PKA inhibitor, H-89, but was unaffected by the PKC inhibitor GF 109203X. In HEK 293 cells, signaling by TP alpha, but not TP beta, was subject to DP-mediated desensitization in a PKA-dependent, PKC-independent manner. U46619-induced signaling by TP(Delta 328), a truncated variant of TP containing only those residues common to TP alpha and TP beta, was insensitive to prior DP stimulation, indicating that the carboxyl terminal tail of TPalpha contains the target site(s) for DP-mediated desensitization. Mutation of Ser(329) to Ala(329) within a consensus PKA site in TP alpha rendered the mutant TP alpha(S329A) insensitive to BW245C-mediated desensitization. Whole cell phosphorylation assays established that TP alpha, but not TP beta or TP alpha(S329A), was subject to DP-mediated phosphorylation and that TP alpha phosphorylation was blocked by the PKA inhibitor H-89. These data establish that TP alpha, but not TP beta, is subject to DP-mediated cross desensitization, which occurs through direct PKA-mediated phosphorylation of TP alpha at Ser(329).

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗