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PubMed2003

Construction of phi29 DNA-packaging RNA monomers, dimers, and trimers with variable sizes and shapes as potential parts for nanodevices.

Recently, DNA and RNA have been under extensive scrutiny with regard to their feasibility as parts in nanotechnology. The DNA-packaging motor of bacterial virus phi29 contains six copies of pRNA molecules, which together form a hexameric ring as a crucial part of the motor. This ring is formed via hand-in-hand interaction by Watson-Crick base pairing of four nucleotides from the left and right loops. Here we report that this pRNA tends to form a circular ring by hand-in-hand contact even when in dimer or trimer form, thus implying that the pRNA structure is flexible. Stable dimers and trimers have been formed from the monomer unit in a protein-free environment with nearly 100% efficiency. The dimers and trimers could be isolated by density gradient sedimentation or purified from native gel. Dimers and trimers were resistant to pH levels as low as 4 and as high as 10, to temperatures as low as -70 degrees C and as high as 80 degrees C, and to high salt concentrations such as 2 M NaCl and 2 M MgCl2. Further study showed that pRNA dimers or trimers with variable lengths could be constructed. Seventy-five bases were found to be the central component in this formation. The elongation of RNA at the 3' end up to 120 bases did not hinder their formation. Other conditions, including the salt requirement for the formation of monomers, dimers, and trimers, have been investigated. RNA monomers, dimers, and trimers with variable lengths are potential parts for nanodevices.

Bacillus Phages↗
PubMed2004

CD45-associated protein inhibits CD45 dimerization and up-regulates its protein tyrosine phosphatase activity.

CD45, a receptor-like protein tyrosine phosphatase (PTP), plays an essential role in lymphocyte development and immune responses. Recent evidence suggests that dimerization of CD45 down-regulates its function. However, the mechanisms by which CD45 dimerization is regulated remain unclear, and there is no direct evidence that the PTP activity of CD45 dimers is less than that of monomers. CD45 in lymphocytes associates with CD45-AP (CD45-associated protein). Here we show that T cells from CD45-AP-null mice have a much higher level of CD45 dimers than those of wild-type mice, suggesting that CD45-AP inhibits CD45 dimer formation. This was confirmed with the use of a novel CD45-AP-null T-cell line, ALST-1, that we established from a spontaneous thymic tumor found in a CD45-AP-null mouse. Transfected CD45-AP inhibited CD45 dimer formation in ALST-1 cells in proportion to the amount of CD45-AP expressed. Finally, with the use of microsomal fractions from both mouse thymocytes and ALST-1 transfectants, the PTP activity of CD45 was found to be significantly lower in CD45-AP-negative cells than in CD45-AP-positive cells. Therefore, our results support a model in which binding of CD45-AP to inactive CD45 dimers converts them to active monomers.

Animals↗
PubMed2006

Impaired RNA incorporation and dimerization in live attenuated leader-variants of SIVmac239.

BACKGROUND: The 5' untranslated region (UTR) or leader sequence of simian immunodeficiency virus (SIVmac239) is multifunctional and harbors the regulatory elements for viral replication, persistence, gene translation, expression, and the packaging and dimerization of viral genomic RNA (vRNA). We have constructed a series of deletions in the SIVmac239 leader sequence in order to determine the involvement of this region in both the packaging and dimerization of viral genomic RNA. We also assessed the impact of these deletions upon viral infectiousness, replication kinetics and gene expression in cell lines and monkey peripheral blood mononuclear cells (PBMC). RESULTS: Regions on both sides of the major splice donor (SD) were found to be necessary for the efficiency and specificity of viral genome packaging. However, stem-loop1 is critical for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the initiation site of SIV-Gag have additive effects on RNA packaging and contribute to a lesser degree to RNA dimerization. The targeted disruption of structures on both sides of the SD also severely impacts viral infectiousness, gene expression and replication in both CEMx174 cells and rhesus PBMC. CONCLUSION: In the leader region of SIVmac239, stem-loop1 functions as the primary determinant for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the translational initiation site of SIV-Gag are classified as secondary determinants and play a role in dimerization. Collectively, these data signify a linkage between the primary encapsidation determinant of SIVmac239 and RNA dimerization.

5' Untranslated Regions↗
PubMed1996

Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors.

Several nuclear receptors including the all-trans retinoic acid receptor RAR, form heterodimers with the 9-cis retinoic acid receptor, RXR. RXR-RAR heterodimers show an impressive flexibility in DNA binding and can recognize palindromic, inverted palindromes and direct repeats of the core half-site sequence AGGTCA. Dimerization interfaces in the DNA-binding domains of RXR, RAR, and thyroid hormone receptor (TR) that promote selective binding to strictly spaced direct repeats have previously been identified. However, an additional dimerization domain is present within the ligand-binding domains (LBDs) of these receptors. Here we localize a transferable 40-amino acid region within the LBDs of RXR, RAR, TR, and chicken ovalbumin upstream promoter transcription factor that is critical for determining identity in the heterodimeric interaction and for high-affinity DNA binding. This region overlaps almost perfectly with a helical segment in the RXR LBD crystal structure that was recently demonstrated to be part of the dimer interface. Our data suggest a sequential pathway for nuclear receptor dimerization whereby the LBD dimerization interface initiates the formation of solution heterodimers that, in turn, acquire the capacity to bind to a number of differently organized repeats. Formation of a second dimer interface within the DNA-binding domain (DBD) restricts receptors to direct repeat targets. Accordingly, the combination of an obligatory (LBD) and an optional (DBD) dimerization domain imparts a dynamic DNA-binding potential to the heterodimerizing receptors that both increases the diversity of the hormonal response as well as providing a restricted set of target sequences in direct repeat elements that ensures physiological specificity.

Amino Acid Sequence↗
PubMed2005

Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation.

Caspases are responsible for the execution of programmed cell death (apoptosis) and must undergo proteolytic activation, in response to apoptotic stimuli, to function. The mechanism of initiator caspase activation has been generalized by the induced proximity model, which is thought to drive dimerization-mediated activation of caspases. The initiator caspase, caspase-9, exists predominantly as a monomer in solution. To examine the induced proximity model, we engineered a constitutively dimeric caspase-9 by relieving steric hindrance at the dimer interface. Crystal structure of the engineered caspase-9 closely resembles that of the wild-type (WT) caspase-9, including all relevant structural details and the asymmetric nature of two monomers. Compared to the WT caspase-9, this engineered dimer exhibits a higher level of catalytic activity in vitro and induces more efficient cell death when expressed. However, the catalytic activity of the dimeric caspase-9 is only a small fraction of that for the Apaf-1-activated caspase-9. Furthermore, in contrast to the WT caspase-9, the activity of the dimeric caspase-9 can no longer be significantly enhanced in an Apaf-1-dependent manner. These findings suggest that dimerization of caspase-9 may be qualitatively different from its activation by Apaf-1, and in conjunction with other evidence, posit an induced conformation model for the activation of initiator caspases.

Caspase 9↗
PubMed2005

Analysis of dimerization determinants of PDE6 catalytic subunits.

An absolute majority of cyclic nucleotide phosphodiesterases (PDEs) form catalytic dimers. The structural determinants and functional significance of PDE dimerization are poorly understood. Furthermore, all known dimeric PDEs with the exception of retinal rod guanosine 3',5'-cyclic-monophosphate PDE (PDE6) are homodimeric enzymes. Rod PDE6 is a catalytic heterodimer composed of alpha- and beta-subunits. Gel filtration, sucrose gradient centrifugation, and immunoprecipitation are standard techniques used to study dimerization of proteins. We successfully applied these methods to investigate dimerization of chimeric proteins between PDE6alphabeta and PDE5, which allowed us to elucidate the structural basis for heterodimerization of rod PDE6. This chapter outlines approaches to the investigation of PDE6 dimerization that can be utilized in a broader analysis of PDE dimerization.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2002

Self-association of disulfonated deuteroporphyrin and its esters in aqueous solution and photosensitized production of singlet oxygen by the dimers.

Dimerization of free acid and ester forms of disulfonated deuteroporphyrin is investigated in aqueous solution by absorbance and fluorescence spectroscopies. The dimerization equilibrium constant increases with the extent of esterification. In phosphate buffer saline (pH 7.4, 20 degrees C), it ranges from 1.4 x 10(6) M(-1) to 7.8 x 10(7) M(-1) for the free acid and the diethyl ester forms, respectively. The dimer formation is favored by an increase of ionic strength, as predicted by the Debye-Hückel law. The dimers display a marked shift to the blue of their Soret band. In agreement with the exciton model, a cofacial stacking of the molecules with some offset is postulated. The sulfonate groups on each molecule are likely to stand on opposite directions to reduce repulsion. Both the analysis of porphyrin self-association and careful examination of the fluorescence excitation spectra show that the dimers of disulfonated deuteroporphyrins do not fluoresce at all. The quantum yield of formation of singlet oxygen by the disulfonated deuteroporphyrins in deuterated methanol is 0.71, a value typical of monomers. In deuterated water, the yield is 0.44 for all the compounds studied though they are dimerized. The fact that nonfluorescent dimers of porphyrins can be efficient photosensitizers is emphasized.

Deuteroporphyrins↗
PubMed2002

CD4 dimers constitute the functional component required for T cell activation.

The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.

Amino Acid Sequence↗
PubMed2003

Human IgG2 can form covalent dimers.

Unlike IgA and IgM, IgG has not yet been shown to form covalent polymers. However in the presence of specific Ag, murine IgG3 has been shown to polymerize through noncovalent interactions. In contrast to the noncovalent oligomers found with murine IgG3, we have detected covalent dimers in three different recombinant human IgG2 Abs produced in myeloma cells. Both IgG2,kappa and IgG2,lambda can form dimers. In addition, analysis of pooled human gamma globulin and several normal sera revealed the presence of IgG2 dimers. The IgG2 dimers are in contrast to the noncovalent IgG dimers found in pooled sera of multiple donors resulting from idiotype/anti-idiotype (Id/anti-Id) interactions. Cyanogen bromide cleavage analysis suggests that one or more Cys residues in the gamma 2 hinge are involved in dimer assembly. The potential role of IgG2 dimers in immunity against carbohydrate Ags is discussed.

Amino Acid Sequence↗
PubMed2003

Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes.

Type 1 diabetes is an autoimmune disorder caused by autoreactive T cells that mediate destruction of insulin-producing beta cells of the pancreas. Studies have shown that T cell tolerance can be restored by inducing a partial or altered signal through the TCR. To investigate the potential of bivalent peptide-MHC class II/Ig fusion proteins as therapeutics to restore Ag-specific tolerance, we have developed soluble peptide I-A(g7) dimers for use in the nonobese diabetic mouse model of diabetes. I-A(g7) dimers with a linked peptide specific for islet-reactive BDC2.5 TCR transgenic CD4(+) T cells were shown to specifically bind BDC2.5 T cells as well as a small population of Ag-specific T cells in nonobese diabetic mice. In vivo treatment with BDC2.5 peptide I-A(g7) dimers protected mice from diabetes mediated by the adoptive transfer of diabetogenic BDC2.5 CD4(+) T cells. The dimer therapy resulted in the activation and increased cell death of transferred BDC2.5 CD4(+) T cells. Surviving cells were hypoproliferative to challenge by Ag and produced increased levels of IL-10 and decreased levels of IFN-gamma compared with cells from control I-A(g7) dimer-treated mice. Anti-IL-10R therapy reversed the tolerogenic effects of the dimer. Thus, peptide I-A(g7) dimers induce tolerance of BDC2.5 TCR T cells through a combination of the induction of clonal anergy and anti-inflammatory cytokines.

Adjuvants, Immunologic↗
PubMed2005

Dimerization of the major birch pollen allergen Bet v 1 is important for its in vivo IgE-cross-linking potential in mice.

In type I allergy, the cross-linking of membrane IgE on B lymphocytes and of cytophilic IgE on effector cells by their respective allergens are key events. For cross-linking two IgE molecules, allergens need at least two epitopes. On large molecules, these could be different epitopes in a multivalent, or identical epitopes in a symmetrical, fashion. However, the availability of epitopes may be limited on small allergens such as Bet v 1, the major birch pollen allergen. The present work analyzes whether dimerization is required for the cross-linking capacity of this allergen. In immunoblots, murine monoclonal and polyclonal human Bet v 1-specific Abs detected, besides a Bet v 1 monomer of 17 kDa, a dimer of 34 kDa. In dynamic light scattering, Bet v 1 appeared as dimers and even multimers, but a single condition could be defined where it behaved exclusively monomerically. Small-angle x-ray scattering of the monomeric and dimeric samples resulted in diagrams agreeing with the calculated models. Circular dichroism measurements indicated that the structure of Bet v 1 was preserved under monomeric conditions. Skin tests in Bet v 1-allergic mice were positive with Bet v 1 dimer, but remained negative using the monomer. Furthermore, in contrast to dimeric Bet v 1, the monomer was less capable of activating murine memory B cells for IgE production in vivo. Our data indicate that the presentation of two identical epitopes by dimerized allergens is a precondition for cross-linking of IgE on mast cells and B lymphocytes.

Allergens↗
PubMed2006

Evidence for a domain-swapped CD4 dimer as the coreceptor for binding to class II MHC.

CD4 is a coreceptor for binding of T cells to APC and the primary receptor for HIV. The disulfide bond in the second extracellular domain (D2) of CD4 is reduced on the cell surface, which leads to formation of disulfide-linked homodimers. A large conformational change must take place in D2 to allow for formation of the disulfide-linked dimer. Domain swapping of D2 is the most likely candidate for the conformational change leading to formation of two disulfide-bonds between Cys130 in one monomer and Cys159 in the other one. Mild reduction of the extracellular part of CD4 resulted in formation of disulfide-linked dimers, which supports the domain-swapped model. The functional significance of dimer formation for coreceptor function was tested using cells expressing wild-type or disulfide-bond mutant CD4. Eliminating the D2 disulfide bond markedly impaired CD4's coreceptor function. Modeling of the complex of the TCR and domain-swapped CD4 dimer bound to class II MHC and Ag supports the domain-swapped dimer as the immune coreceptor. The known involvement of D4 residues Lys318 and Gln344 in dimer formation is also accommodated by this model. These findings imply that disulfide-linked dimeric CD4 is the preferred coreceptor for binding to APC.

Animals↗
PubMed1999

Dimer formation by tRNAs.

Available data on formation of dimers and other oligomers by "mature" tRNAs and the transcripts of their genes show that the dimers may be formed in vitro during the purification of individual tRNAs as well as on heating and subsequent cooling of tRNA preparations. The functional activity of dimers varies for different tRNAs. Structural analysis of tRNAs that are able or unable to form dimers suggests the importance of the hairpin melting temperature for dimer formation. Pathways of dimer formation and specific structural features of tRNA dimers are discussed.

Amino Acyl-tRNA Synthetases↗
PubMed2001

Covalent and noncovalent interactions mediate metabotropic glutamate receptor mGlu5 dimerization.

Some, perhaps all, G protein-coupled receptors form homo- or heterodimers. We have shown that metabotropic glutamate receptors are covalent dimers, held together by one or more disulfide bonds near the N terminus. Here we report how mutating cysteines in this region affect dimerization and function. Covalent dimerization is preserved when cysteines 57, 93, or 99 are mutated but lost with replacement at 129. Coimmunoprecipitation under nondenaturing conditions indicates that the C[129]S mutant receptor remains a dimer, via noncovalent interactions. Both C[93]S and C[129]S bind [3H]quisqualate, whereas binding to C[57]S or C[99]S mutants is absent or greatly attenuated. The C[93]S and C[129]S receptors have activity similar to wild-type when assayed by fura-2 imaging of intracellular calcium in human embryonic kidney cells or electrophysiologically in Xenopus laevis oocytes. In contrast, C[57]S or C[99]S are less active in both assays but do respond with higher glutamate concentrations in the oocyte assay. These results demonstrate that 1) covalent dimerization is not critical for mGlu5 binding or function; 2) mGlu5 remains a noncovalent dimer even in the absence of covalent dimerization; and 3) high-affinity binding requires Cys-57 and Cys-99.

Animals↗
PubMed2006

Structure of T4 pyrimidine dimer glycosylase in a reduced imine covalent complex with abasic site-containing DNA.

The base excision repair (BER) pathway for ultraviolet light (UV)-induced cyclobutane pyrimidine dimers is initiated by DNA glycosylases that also possess abasic (AP) site lyase activity. The prototypical enzyme known to catalyze these reactions is the T4 pyrimidine dimer glycosylase (T4-Pdg). The fundamental chemical reactions and the critical amino acids that lead to both glycosyl and phosphodiester bond scission are known. Catalysis proceeds via a protonated imine covalent intermediate between the alpha-amino group of the N-terminal threonine residue and the C1' of the deoxyribose sugar of the 5' pyrimidine at the dimer site. This covalent complex can be trapped as an irreversible, reduced cross-linked DNA-protein complex by incubation with a strong reducing agent. This active site trapping reaction is equally efficient on DNA substrates containing pyrimidine dimers or AP sites. Herein, we report the co-crystal structure of T4-Pdg as a reduced covalent complex with an AP site-containing duplex oligodeoxynucleotide. This high-resolution structure reveals essential precatalytic and catalytic features, including flipping of the nucleotide opposite the AP site, a sharp kink (approximately 66 degrees ) in the DNA at the dimer site and the covalent bond linking the enzyme to the DNA. Superposition of this structure with a previously published co-crystal structure of a catalytically incompetent mutant of T4-Pdg with cyclobutane dimer-containing DNA reveals new insights into the structural requirements and the mechanisms involved in DNA bending, nucleotide flipping and catalytic reaction.

Base Sequence↗
PubMed2002

The sensitivity and specificity of a red blood cell agglutination D-dimer assay for venous thromboembolism when performed on venous blood.

BACKGROUND: Studies evaluating the accuracy of the SimpliRED D-dimer assay for venous thromboembolism (VTE) have used a capillary fingerstick blood sample, which requires the test to be performed immediately at the bedside. Initial studies showed a sensitivity for VTE of 90% to 95% when the assay was performed by a finite number of experienced health care workers. However, because of the test's subjectivity, misinterpretation of the result is possible when performed by inexperienced staff. Recent reports by other investigators indicated a low sensitivity of this assay for VTE and noted a reduction in sensitivity (84%) for pulmonary embolism. OBJECTIVE: To determine the sensitivity and specificity of the D-dimer test performed in the laboratory by experienced technologists on venous whole-blood samples in routine collection tubes. If D-dimer testing results accurately detect VTE when performed in this manner, concerns about the sensitivity of this assay would be solved. METHODS: One hundred forty-eight consecutive patients with suspected VTE underwent D-dimer testing at the bedside using a fingerstick sample and venous blood collected into a plain tube. Venous blood was also collected into tubes containing tri-potassium EDTA, sodium citrate, or a combination of lithium and heparin for D-dimer testing in the laboratory. In addition, the EDTA tube was refrigerated overnight at 4 degrees C for retesting at approximately 24 hours. The presence or absence of VTE was determined by means of objective results of testing and a 3-month follow-up. RESULTS: Thirty-four subjects (23%) had confirmed VTE (25 with deep vein thrombosis; 9 with pulmonary embolism). All laboratory venous blood D-dimer results showed sensitivities of 97%, specificities of 61% to 64%, and negative predictive values of 99%, compared with 88%, 71%, and 95%, respectively, when the results were obtained by means of fingerstick at the bedside. CONCLUSIONS: The SimpliRED D-dimer assay performed in the laboratory on venous blood, collected into any of 3 routine laboratory tubes, is sensitive and moderately specific for VTE. Based on this study, immediate bedside testing (particularly by inexperienced personnel) under suboptimal conditions is unnecessary. Furthermore, the high sensitivity of refrigerated EDTA samples allows specimens to be stored or transported (on ice at 4 degrees C) for testing for 24 hours after collection.

Erythrocytes↗
PubMedDate not supplied

Clinical usefulness of D-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism.

BACKGROUND: We evaluated whether a highly sensitive D-dimer test is clinically useful and safe for ruling out pulmonary embolism (PE) in patients with a high clinical probability and whether adopting different cutoff values according to the clinical probability category might increase the proportion of patients in whom PE is ruled out. METHODS: We retrospectively analyzed the databases of 2 outcome studies on the diagnosis of PE with a 3-month follow-up that included 1409 patients. We evaluated the usefulness of D-dimer testing by calculating the number needed to test to rule out one PE, and its safety by measuring the 3-month thromboembolic risk in patients not treated by anticoagulant agents based on a normal D-dimer level. RESULTS: The sensitivity of D-dimer was 100% in all clinical probability categories, but the number needed to test increased with increasing clinical probability of PE. The 95% confidence interval (0%-23%) of the 3-month thromboembolic risk (0%) among 13 of 121 patients with a normal D-dimer level and a high clinical probability of PE was wide. Increasing the cutoff value to 700 mug/L in patients with a low clinical probability would rule out PE in an additional 5% of the entire patient cohort at the expense of a lower sensitivity (93% [95% confidence interval, 83%-97%]). CONCLUSIONS: The safety of D-dimer testing in patients with a high clinical probability of PE is not established, and testing results are rarely negative in such patients. Increasing the enzyme-linked immunosorbent assay D-dimer cutoff value only marginally increased the test's usefulness.

Aged↗
PubMed2001

Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study.

CONTEXT: A previous study suggested that the combination of a normal D-dimer assay and normal alveolar dead-space fraction is a highly sensitive screening test for pulmonary embolism (PE). OBJECTIVE: To determine if the combination of a normal alveolar dead-space fraction (volume of alveolar dead space/tidal volume </=20%) and a normal whole-blood agglutination D-dimer assay can exclude PE in emergency department (ED) patients. DESIGN: Prospective, noninterventional study conducted in 1998-1999. Study data were obtained prior to standard testing for PE, consisting of radionuclide lung scanning or contrast-enhanced computed tomography and 6-month follow-up plus selective use of venous ultrasonography and pulmonary angiography. Imaging studies were interpreted by blinded observers. SETTING: Six urban teaching hospitals in the United States. PATIENTS: A total of 380 hemodynamically stable ED patients aged 18 years or older with suspected acute PE. MAIN OUTCOME MEASURES: Sensitivity and specificity for PE with a positive test defined as having either alveolar dead-space fraction or D-dimer assay results abnormal. Alveolar dead-space fraction was determined by subtracting airway dead space from physiological dead space (determined using the modified Bohr equation) and D-dimer assay, assayed at bedside using 20 microL of arterial blood. RESULTS: Pulmonary embolism was diagnosed in 64 patients (16.8%), of those 20 had an abnormal D-dimer assay result, 3 had an abnormal alveolar dead-space fraction, 40 had abnormal results in both, and 1 had normal results for both tests. The sensitivity for diagnosis of PE was 98.4% (95% confidence interval [CI], 91.6%-100.0%). Among the 316 patients without PE, both D-dimer and dead-space results were normal in 163, for a specificity of 51.6% (95% CI, 46.1%-57.1%). Posterior probability of PE with normal results on both tests was 0.75% (95% CI, 0%-3.4%). CONCLUSION: In this multicenter study of ED patients, a normal D-dimer assay result plus a normal alveolar dead-space fraction was associated with a low prevalence of PE.

Adult↗