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At least 451 records · Page 25Linked to original sources
PubMed1994

Tissue-specific and temporal regulation of a beta-conglycinin gene: roles of the RY repeat and other cis-acting elements.

Upstream regulatory sequences (URS) of the gene that encodes the alpha' subunit of beta-conglycinin, the 7S soybean seed storage protein, includes two RY repeat elements. The role of RY elements and sequences that bind soybean embryo factors 3 and 4 (SEF3 and SEF4; Allen et al., Plant Cell 1 (1989) 623-631) in regulating expression of the promoter was studied following site directed mutagenesis. Specific mutations introduced into these sequences abolished the in vitro binding activities of SEF3 and SEF4. The biological activities resulting from the mutations were determined in transgenic plants using two chimeric promoters comprising sequences from the CaMV 35S promoter and the alpha' subunit promoter. The uidA reporter gene was used to assess the levels of gene expression in transgenic plants. The mutations in the RY element and SEF3 and SEF4 binding sites had little effect on expression of the alpha' promoter. By contrast, mutations in the RY element had significant effect on gene expression when the URS from the alpha' promoter was ligated upstream of the core 35S promoter. Mutations in the RY element abolished the seed specific enhancing activity of the alpha' URS and caused expression of the chimeric promoter in leaves. These results indicate that the RY element plays a key role in seed-specific gene regulation in coordination with other cis-acting elements.

Antigens, Plant↗
PubMed1993

Three-dimensional structure of the tetragonal crystal form of egg-white avidin in its functional complex with biotin at 2.7 A resolution.

The three-dimensional structure of hen egg-white avidin, crystallized in a tetragonal crystal form, has been solved at 2.7 A resolution by molecular replacement methods. After refinement the crystallographic R-factor is 16.8%, for the 7255 reflections in the 10.0 to 2.7 A resolution range. The asymmetric unit contains two avidin polypeptide chains (M(r) 2 x 15,600), which build up the functional tetramer through a crystallographic 2-fold axis parallel to the c unit cell direction. The avidin tetramer has almost exact 222 molecular symmetry; the three possible dimers display quite distinct packing interfaces. Each protomer is organized in an eight-stranded antiparallel orthogonal beta-barrel, with extended loop regions. The avidin binding site within each promoter is located in a deep pocket, at the center of the barrel, displaying both hydrophobic and polar residues for recognition of the tightly bound vitamin. Two Trp residues, Trp70 and Trp97, and Phe79 are in close contact with biotin. Moreover, the binding pocket is partly closed in its outer rim by residue Trp110 of a neighboring subunit. Once bound, biotin is almost completely buried in the protein core, with the exception of the valeryl side-chain carboxylate group which is exposed to solvent, hydrogen bonds to residues Ala39, Thr40 and Ser75, and triggers the formation of a network of hydrogen bonded water molecules. Modeling of synthetic biotin analogues allows us to rationalize functional data available for the binding of these compounds, and to analyze them in terms of biotin recognition mechanism. Hen egg-white avidin shows clear structural homology to streptavidin, from Streptomyces avidinii, but significant deviations can be observed in some regions.

Amino Acid Sequence↗
PubMed2000

Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis.

The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of translocations associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code) and R139G, (single-letter amino acid codes) were identified in 2 cases of myelodysplastic syndrome (MDS) by means of the reverse transcriptase-polymerase chain reaction single-strand conformation polymorphism method. Both mutations are present in the region encoding the runt domain of AML1 and cause loss of the DNA-binding ability of the resultant products. Of these mutants, V105ter has also lost the ability to heterodimerize with polyomavirus enhancer binding protein 2/core binding factor beta (PEBP2beta/CBFbeta). On the other hand, the R139G mutant acts as a dominant negative inhibitor by competing with wild-type AML1 for interaction with PEBP2beta/CBFbeta. This study is the first report that describes mutations of AML1 in patients with MDS and the mechanism whereby the mutant acts as a dominant negative inhibitor of wild-type AML1.

Amino Acid Substitution↗
PubMed2004

Clinical significance of minimal residual disease in childhood acute myeloid leukemia.

Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia. Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers. Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD. Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002. After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8, PML/RAR alpha, and MYH11/CBF beta were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 10(3) copies/microgram RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients, PML/RAR alpha was expressed in 3 patients, and MYH11/CBF beta was expressed in 1 patient. Four of the 8 patients with AML1/MTG8 expression and all 3 with PML/RAR alpha expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed pesistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR alpha and MYH11/CBF beta fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% +/- 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes. Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.

Acute Disease↗
PubMed1993

The role of viral enhancer "core" motif-related sequences in regulating T cell receptor-gamma and -delta gene expression.

T cells express clonally distributed alpha beta or gamma delta Ag receptor heterodimers. Transcriptional enhancers for the genes of all four subunits are active in both gamma delta and alpha beta T cells, but are less active or inactive in other cells. Conserved sequence motifs are present in all four enhancers, suggesting that common transcription factors regulate TCR gene expression. One of these motifs in the gamma 3 site of the TCR-gamma enhancer is similar to motifs found in several other lymphoid-specific and viral enhancers. This conserved "core" sequence is present in the enhancers of Moloney and SL3-3 murine leukemia viruses, important for transcription in T cells and in determining disease specificity. Here we characterize the gamma 3 site of the gamma enhancer and a corresponding homologous site, delta E3, of the TCR-delta enhancer. Our results suggest that the core site is critical for activity of the 200-bp gamma enhancer fragment and of the gamma 3 and delta E3 sites. Furthermore, we identify a nuclear factor in human T cell lines that specifically binds the core region in these and several other core-containing enhancers. This factor may be identical to or related to a purified bovine nuclear core binding factor that binds the core region of the Moloney murine leukemia virus enhancer, gamma 3 and delta E3 sites, suggesting that similar proteins regulate the TCR-gamma, delta and Moloney murine leukemia virus enhancers. Other sequences in the gamma 3 site upstream of the core sequence are also critical for activity in T cells, suggesting that at least two different factors are required for functional activity of the gamma 3 site.

Animals↗
PubMed1996

DNA-binding domain of AML1, expressed in t(8;21) and t(3;21) myeloid leukemias, inhibits PEBP2/CBF DNA-binding but is not sufficient to transform 32D cl3 myeloid cells.

Truncated AML1 proteins are predicted to be expressed from out-of-frame AML1 transcripts present in myeloid leukemia cells harboring t(8;21) and t(3;21). To test whether these proteins, consisting of almost exclusively an N-terminal AML1 DNA-binding domain, interfere with myeloid differentiation we expressed a similar truncated AML1 protein in 32D cl3 myeloid cells. In all clones examined, the ectopically expressed truncated AML1 protein prevented binding of endogenous PEBP2/CBFs to DNA, possibly by interacting with all available CBF beta subunits. However, compared to control clones, the 32D cl3 clones expressing truncated AML1 remained IL-3 dependent for survival, proliferated similarly in low and high concentrations of IL-3, and differentiated similarly upon transfer to G-CSF. Thus, truncated AML1 proteins may contribute to myeloid leukemogeneis by inhibiting PEBP2/CBF activities, although contributions from other oncoproteins are likely required as well.

Animals↗
PubMed1994

Pleckstrin homology (PH) domains in signal transduction.

A diverse array of molecules involved in signal transduction have recently been recognised as containing a new homology domain, the pleckstrin homology (PH) domain. These include kinases (both serine/threonine and tyrosine specific), all currently known mammalian phospholipase Cs, GTPases, GTPase-activating proteins, GTPase-exchange factors, "adapter" proteins, cytoskeletal proteins, and kinase substrates. This has sparked a new surge of research into elucidating its structure and function. The NMR solution structure of the PH domains of beta-spectrin and pleckstrin (the N-terminal domain) both display a core consisting of seven anti-parallel beta-sheet strands. The carboxy terminus is folded into a long alpha-helix. The molecule is electrostatically polarised and contains a pocket which may be involved in the binding of a ligand. The PH domains overall topological relatedness to the retinoid binding protein family of molecules would suggest a lipid ligand could bind to this pocket. The prime function of the PH domain still remains to be elucidated. However, it has been shown to be important in signal transduction, most probably by mediating protein-protein interactions. An extended PH domain of the beta-adrenergic receptor kinase (beta ARK), as well as that of several other molecules, can bind to beta gamma subunits of the heterotrimeric G-proteins. The possibility that the PH domain, which is found in so many signalling molecules, being generally involved in beta gamma binding is provocative of implicating these proteins in G-protein signal transduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2004

Phosphophoryn regulates the gene expression and differentiation of NIH3T3, MC3T3-E1, and human mesenchymal stem cells via the integrin/MAPK signaling pathway.

Extracellular matrix proteins (ECMs) serve as both a structural support for cells and a dynamic biochemical network that directs cellular activities. ECM proteins such as those of the SIBLING family (small integrin-binding ligand glycoprotein) could possess inherent growth factor activity. In this study, we demonstrate that exon 5 of dentin matrix protein 3 (phosphophoryn (PP)), a non-collagenous dentin ECM protein and SIBLING protein family member, up-regulates osteoblast marker genes in primary human adult mesenchymal stem cells (hMSCs), a mouse osteoblastic cell line (MC3T3-E1), and a mouse fibroblastic cell line (NIH3T3). Quantitative real-time PCR technology was used to quantify gene expression levels of bone markers such as Runx2, Osx (Osterix), bone/liver/kidney Alp (alkaline phosphatase), Ocn (osteocalcin), and Bsp (bone sialoprotein) in response to recombinant PP and stably transfected PP. PP up-regulated Runx2, Osx, and Ocn gene expression. PP increased OCN protein production in hMSCs and MC3T3-E1. ALP activity and calcium deposition was increased by PP in hMSC. Furthermore, an alpha(v)beta(3) integrin-blocking antibody significantly inhibited recombinant PP-induced expression of Runx2 in hMSCs, suggesting that signaling by PP is mediated through the integrin pathway. PP was also shown to activate p38, ERK1/2, and JNK, three components of the MAPK pathway. These data demonstrate a novel signaling function for PP in cell differentiation beyond the hypothesized role of PP in biomineralization.

Alkaline Phosphatase↗
PubMed1994

Transcriptional activation by hypersensitive site three of the human beta-globin locus control region in murine erythroleukemia cells.

In this paper we describe a complete deletional analysis of hypersensitive site three (HS3) of the human beta-globin Locus Control Region (LCR). The previously defined core fragment consists of 6 footprinted regions, with multiple binding sites for the erythroid-specific factor GATA-1 and G-rich motifs that can interact with ubiquitous factors such as Sp1 and TEF-2. We show in this paper that the 5' half of this fragment is the most important for activity in murine erythroleukemia (MEL) cells. A fragment containing footprints 1-4 can stimulate transcription of a linked human beta-globin gene to levels of about 40% of that obtained with footprints 1-6. Constructs containing either footprints 1-3 or 3-6 cannot be distinguished from the beta-globin gene alone. We further show that binding sites for the erythroid-specific factor NF-E2 can co-operatively interact with parts of the HS3 core fragment, and that HS3 requires elements upstream from -103 in the human beta-globin promoter for full activity. The importance of these results is discussed in the context of the regulation of the genes in the human beta-globin cluster.

Animals↗
PubMed1995

Functional domains of the t(8;21) fusion protein, AML-1/ETO.

The AML-1/ETO fusion protein is created by the (8;21) translocation, the second most frequent chromosomal abnormality associated with acute myeloid leukemia. In the fusion protein the AML-1 runt homology domain, which is responsible for DNA binding and CBF beta interaction, is linked to ETO, a gene of unknown function. The primary sequences of the runt homology domain indicates no known DNA binding motifs, but is predicted to contain six beta-strands, two alpha-helices and a nucleotide binding motif. Mutagenesis of AML-1/ETO was performed to delimit the functional domains of the chimeric protein. Most mutations in the runt homology domain that resulted in reduced CBF beta binding also inhibited DNA binding, indicating that the DNA and CBF beta binding sequences are tightly linked. However, these activities were separated by a point mutation of residue 144, within the putative ATP binding motif, which nearly eliminated DNA binding, but did not affect CBF beta binding. Random mutagenesis identified the hydrophobic face of the amphipathic fifth beta-strand, adjacent to the putative ATP binding motif, as critical for both DNA and CBF beta binding. C-terminal deletion mutants of AML-1/ETO indicated that ETO sequences are essential for interference with AML-1B-mediated transcriptional activation, and that residue 540 defines the C-terminal boundary of a potential repression domain. Thus, these mutational analyses define the regions of AML-1/ETO which regulate its function and that may be important in promoting leukemia.

Adenosine Triphosphate↗
PubMed2004

Isolation and functional analysis of Arabidopsis stress-inducible NAC transcription factors that bind to a drought-responsive cis-element in the early responsive to dehydration stress 1 promoter.

The MYC-like sequence CATGTG plays an important role in the dehydration-inducible expression of the Arabidopsis thaliana EARLY RESPONSIVE TO DEHYDRATION STRESS 1 (ERD1) gene, which encodes a ClpA (ATP binding subunit of the caseinolytic ATP-dependent protease) homologous protein. Using the yeast one-hybrid system, we isolated three cDNA clones encoding proteins that bind to the 63-bp promoter region of erd1, which contains the CATGTG motif. These three cDNA clones encode proteins named ANAC019, ANAC055, and ANAC072, which belong to the NAC transcription factor family. The NAC proteins bound specifically to the CATGTG motif both in vitro and in vivo and activated the transcription of a beta-glucuronidase (GUS) reporter gene driven by the 63-bp region containing the CATGTG motif in Arabidopsis T87 protoplasts. The expression of ANAC019, ANAC055, and ANAC072 was induced by drought, high salinity, and abscisic acid. A histochemical assay using P(NAC)-GUS fusion constructs showed that expression of the GUS reporter gene was localized mainly to the leaves of transgenic Arabidopsis plants. Using the yeast one-hybrid system, we determined the complete NAC recognition sequence, containing CATGT and harboring CACG as the core DNA binding site. Microarray analysis of transgenic plants overexpressing either ANAC019, ANAC055, or ANAC072 revealed that several stress-inducible genes were upregulated in the transgenic plants, and the plants showed significantly increased drought tolerance. However, erd1 was not upregulated in the transgenic plants. Other interacting factors may be necessary for the induction of erd1 in Arabidopsis under stress conditions.

Abscisic Acid↗
PubMed2000

Nuclear import and subnuclear localization of the proto-oncoprotein ETO (MTG8).

ETO (MTG8) was first described due to its involvement in the (8;21) translocation frequently observed in acute myeloid leukemias. In the t(8;21) the AML1 gene on chromosome 21 is fused to ETO on chromosome 8. The resultant hybrid protein is comprised of the DNA binding domain of AML-1 and the majority of ETO. This study examines the subnuclear distributions of ETO, AML-1B and AML-1/ETO proteins fused to green fluorescence protein in living cells using fluorescence microscopy. Further, we identified a 40 amino acid portion of ETO (amino acids 241-280) that was sufficient to cause nuclear import of green fluorescent protein. Mutational analysis demonstrated that lysine 265 and/or arginine 266 were required for nuclear import of ETO, but that the surrounding basic residues were not critical. ETO interacted with the nuclear import proteins importin-alpha and beta in vitro, and mutations in ETO that abolish nuclear localization also abolished the in vitro interaction with importin-alpha and beta. These data suggest that ETO enters the nucleus via an importin-mediated pathway. Additionally, ETO and AML-1/ETO co-localized to punctate nuclear bodies distinct from those containing promyelocytic leukemia protein. Nuclear body formation was dependent upon a region of ETO N-terminal to the nuclear localization signal. Thus, ETO and AML-1/ETO reside in potentially novel subnuclear compartments.

Amino Acid Sequence↗
PubMed2004

Steroid effects on osteogenesis through mesenchymal cell gene expression.

We have studied the mechanism of steroid-induced osteonecrosis by examining the effect of dexamethasone on a multipotential cell line, D1, which is derived from bone marrow and is capable of differentiating into either the osteoblast or the adipocyte lineage. The expression of bone cell and fat cell transcription factors Cbfa1/Runx2 and PPARgamma2, were determined. Osteocalcin promoter activity was measured by co-transfecting the cells with the phOC-luc and pSV beta-Gal plasmids. Dexamethasone increased PPARgamma2 gene expression 2-fold, while Cbfa1/Runx2 gene expression and osteocalcin promoter activity decreased by 50-60%, and VEGF protein, measured by ELISA, decreased by 55%. These changes indicate enhanced adipogenesis and decreased osteogenesis by mesenchymal cells in vitro, together with a decrease in VEGF, a potent angiogeneic factor, suggesting that dexamethasone may shunt uncommitted osteoprogenitor cells in marrow from osteoblastic differentiation into the adipocytic pathway, leading to diminished vascularization and eventual osteonecrosis.

Adipocytes↗
PubMed2002

Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway.

Precise regulation of the evolutionarily conserved hypoxia-inducible transcription factor (HIF) ensures proper adaptation to variations in oxygen availability throughout development and into adulthood. Oxygen-dependent regulation of HIF stability and activity are mediated by hydroxylation of conserved proline and asparagine residues, respectively. Because the relevant prolyl and asparginyl hydroxylases use O(2) to effect these posttranslational modifications, these enzymes are implicated as direct oxygen sensors in the mammalian hypoxic response pathway. Here we present the structure of factor-inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved in hypoxic signaling. Hydroxylation of the C-terminal transactivation domain (CTAD) of HIF by FIH-1 prevents CTAD association with transcriptional coactivators under normoxic conditions. Consistent with other structurally known hydroxylases, FIH-1 is comprised of a beta-strand jellyroll core with both Fe(II) and the cosubstrate 2-oxoglutarate bound in the active site. Details of the molecular contacts at the active site of FIH-1 have been elucidated and provide a platform for future drug design. Furthermore, the structure reveals the presence of a FIH-1 homodimer that forms in solution and is essential for FIH activity.

Amino Acid Sequence↗
PubMed1994

Molecular dissection of GT-1 from Arabidopsis.

We isolated and characterized an Arabidopsis cDNA encoding the DNA binding protein GT-1. This protein factor, which contains 406 amino acids, is highly homologous to the previously described tobacco DNA binding protein GT-1a/B2F but is 26 amino acids longer. Recombinant Arabidopsis GT-1, which was obtained from in vitro translation, bound to probes consisting of four copies of pea small subunit of ribulose bisphosphate carboxylase rbcS-3A box II and required the same GGTTAA core binding site as the binding activity of an Arabidopsis nuclear protein preparation. However, unlike the truncated tobacco GT-1a prepared from Escherichia coli extracts, the full-length Arabidopsis GT-1 bound to pea rbcS-3A box III and Arabidopsis chlorophyll a/b binding protein CAB2 light-responsive elements, both of which contain GATA motifs. Deletion and mutational analyses suggested that the predicted trihelix region of GT-1 is essential for DNA binding. Moreover, GT-1 binds to target DNA as a dimer, and its C-terminal region contains a putative dimerization domain that enhances the binding activity. Transient expression of the GT-1::beta-glucuronidase fusion protein in onion cells revealed the presence of a nuclear localization signal(s) within the first 215 amino acids of GT-1.

Amino Acid Sequence↗
PubMed2006

RUNX3: a new player in myeloid gene expression and immune response.

RUNX transcription factors function as scaffolds for interaction with various coregulatory proteins during developmental processes such as hematopoiesis, neurogenesis, and osteogenesis. The current view places RUNX proteins within the TGF-beta signaling pathway, although each one exhibits cell- and tissue-specific functions. In the case of RUNX3, recent data have suggested its function as a tumor suppressor factor and highlighted its involvement in immune cell differentiation and activation. The molecular mechanisms for the pleiotropic effects of Runx3 deficiency are not completely understood. The present article will summarize the known functional activities of RUNX3, emphasizing its role in myeloid cell gene expression and its potential contribution to the migratory and adhesive capabilities of this cell lineage.

Animals↗
PubMed1995

Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias.

Karyotypic detection of chromosomal 16 abnormalities classically associated with AML M4Eo can be difficult. Characterization of the two genes involved in the inv(16)(p13q22), CBF beta and MYH11, has allowed the detection of fusion transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR). We have analyzed CBF beta-MYH11 fusion transcripts by RT-PCR in myelomonocytic leukemias, with or without eosinophilia, to determine whether their presence correlates with morphology. Fifty-three cases (11 AML M4Eo; 1 AML M4 with atypical abnormal eosinophils (AML M4 "Eo"); 29 AML M4; 8 AML M5; 3 CMML; and 1 AML M2 with eosinophilia) were analyzed. All 11 typical AML M4Eo were CBF beta-MYH11 positive. The single case of AML M4 with distinctive eosinophil abnormalities was negative by karyotype, RT-PCR and fluorescent in situ hybridization (FISH). Three of 29 (10%) AML M4 without abnormal eosinophils were CBF beta-MYH11 positive, 1 of which did not show any apparent chromosome 16 abnormalities by classical metaphase analysis (2 not tested). Both cases tested also showed MYH11 genomic rearrangement. None of the other leukemias were RT-PCR positive. Follow-up of three patient showed residual positivity in apparent complete remission. These data show that CBF beta-MYH11 fusion transcripts occur not only in the vast majority of typical AML M4Eo, but also in approximately 10% of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Taken together with the detection of CBF beta-MYH11 transcripts in the absence of apparent chromosome 16 abnormalities by classical banding techniques, these data show that additional screening by either RT-PCR or FISH should be performed in all AML M4, regardless of morphologic features, to allow accurate evaluation of the prognostic importance of this fusion transcript.

Adolescent↗
PubMed2002

BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2.

The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.

Amino Acid Sequence↗