Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation and the development of the floral organs require an intercalate expression of organ-specific genes. At the same time, meristem-specific genes are repressed to complete the differentiation of the organs in the floral whorls. In an Arabidopsis activation tagging population, a mutant affected in inflorescence architecture was identified. This gain-of-function mutant, designated downwards siliques1 (dsl1-D), has shorter internodes and the lateral organs such as flowers are bending downwards, similar to the loss-of-function brevipedicellus (bp) mutant. The affected gene in dsl1-D appeared to be ASYMMETRIC LEAVES2-LIKE1 (ASL1)/LATERAL ORGAN BOUNDARIES domain gene 36 (LBD36), which is a member of the ASYMMETRIC LEAVES2 (AS2)/LATERAL ORGAN BOUNDARIES (LOB) domain gene family. Analysis of the loss-of-function mutant asl1/lbd36 did not show morphological aberration. Double mutant analysis of asl1/lbd36 together with as2, the ASL1/LBD36 closest homologue, demonstrates that these two members of the AS2/LOB family act partially redundant to control cell fate determination in Arabidopsis petals. Moreover, molecular analysis revealed that overexpression of ASL1/LBD36 leads to repression of the homeobox gene BP, which supports the model that an antagonistic relationship between ASL/LBD and homeobox members is required for the differentiation of lateral organs.
Plant Mol Biol 2005 Mar
PMID:ASYMMETRIC LEAVES2-LIKE1 gene, a member of the AS2/LOB family, controls proximal-distal patterning in Arabidopsis petals. 1582 80

Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs are deposits of starch-like polyglucosans, insufficiently branched and hence insoluble glycogen molecules resulting from glycogen synthase (GS) overactivity relative to glycogen branching enzyme activity. We previously made the unexpected observation that laforin, in the absence of which polyglucosans accumulate, specifically binds polyglucosans. This suggested that laforin's role is to detect polyglucosan appearances during glycogen synthesis and to initiate mechanisms to downregulate GS. Glycogen synthase kinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylation of GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylation at multiple sites. Glucose-6-phosphate is a potent allosteric activator of GS. Glucose-6-phosphate levels are high when the amount of glucose increases and its activation of GS overrides any phospho-inhibition. Here, we show that laforin is a GSK3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. We also show that laforin interacts with malin and that malin is an E3 ubiquitin ligase that binds GS. We propose that laforin, in response to appearance of polyglucosans, directs two negative feedback pathways: polyglucosan-laforin-GSK3-GS to inhibit GS activity and polyglucosan-laforin-malin-GS to remove GS through proteasomal degradation.
Hum Mol Genet 2005 Sep 15
PMID:Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. 1611 20

The plant specific LATERAL ORGAN BOUNDARIES (LOB) domain (LBD) gene family has a potential role in lateral organ development. Thirty-five LBD genes in a japonica rice (Nipponbare) (designated OsJLBD) and in an indica rice (9311) (designated OsILBD) were identified based on the current databases of the two rice subspecies. A new rice LBD gene with two LOB domains and two predicted coiled coil structures in both subspecies was found, which is not found in other plant species based on the current NCBI Genbank database. OsJLBD and OsILBD genes have similar chromosomal distribution pattern. Both OsJLBD and OsILBD genes can be divided into 7 subclasses (classes Ia-e, II and III (see )) and no subclass-specific expression pattern was observed. No introns have been predicted in all class Ie genes in both OsJLBD and OsILBD subfamilies. The genome and tandem duplication has contributed to the neofunctionalization and formation of new rice subclasses, but the mechanism of diploidization and limited tandem duplication have contributed to fewer LBD genes in rice than in Arabidopsis. Functional studies of genes in subclasses may help to determine whether special sequence structure (intron-exon, spacing characters of motifs) has caused special expression pattern of subclasses.
Mol Phylogenet Evol 2006 Apr
PMID:Comparison and evolution analysis of two rice subspecies LATERAL ORGAN BOUNDARIES domain gene family and their evolutionary characterization from Arabidopsis. 1629 Jan 86

The thyroid hormone receptor (TR) D-domain links the ligand-binding domain (LBD, EF-domain) to the DNA-binding domain (DBD, C-domain), but its structure, and even its existence as a functional unit, are controversial. The D domain is poorly conserved throughout the nuclear receptor family and was originally proposed to comprise an unfolded hinge that facilitates rotation between the LBD and the DBD. Previous TR LBD structures, however, have indicated that the true unstructured region is three to six amino acid residues long and that the D-domain N terminus folds into a short amphipathic alpha-helix (H0) contiguous with the DBD and that the C terminus of the D-domain comprises H1 and H2 of the LBD. Here, we solve structures of TR-LBDs in different crystal forms and show that the N terminus of the TRalpha D-domain can adopt two structures; it can either fold into an amphipathic helix that resembles TRbeta H0 or form an unstructured loop. H0 formation requires contacts with the AF-2 coactivator-binding groove of the neighboring TR LBD, which binds H0 sequences that resemble coactivator LXXLL motifs. Structural analysis of a liganded TR LBD with small angle X-ray scattering (SAXS) suggests that AF-2/H0 interactions mediate dimerization of this protein in solution. We propose that the TR D-domain has the potential to form functionally important extensions of the DBD and LBD or unfold to permit TRs to adapt to different DNA response elements. We also show that mutations of the D domain LXXLL-like motif indeed selectively inhibit TR interactions with an inverted palindromic response element (F2) in vitro and TR activity at this response element in cell-based transfection experiments.
J Mol Biol 2006 Jul 14
PMID:Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. 1678 32

A FTZ-F1-related orphan nuclear receptor SmFTZ-F1alpha was previously identified from Schistosoma mansoni. The deduced SmFTZ-F1alpha protein contains a highly conserved DNA binding domain (DBD, C domain), a less conserved ligand binding domain (LBD, E domain) and three highly variable regions, the N-terminal A/B domain (108 aa), a large hinge region (D domain, 1027 aa) and an F domain (220 aa). Herein, we characterize the DNA binding properties and the transactivation activity of SmFTZ-F1alpha. In in vitro assays, SmFTZ-F1alpha bound as a monomer to a response element (FF1RE: TCAAGGTCA) recognized by mammalian steroidogenic factor 1 (SF-1), and to related sequences (p14: TTAAGGTCA and SmFF1a-2: CGAAGGTCA) derived from known schistosome gene promoters. Competition assays with p14 oligonucleotides containing a single mutation at each nucleotide position defined the optimum DNA sequence required for SmFTZ-F1alpha binding. The optimal consensus sequence for SmFTZ-F1alpha binding is TN(A/G)AGGTC(A/G) (N: any base). This sequence is similar but not identical to the SF-1 response element (SFRE) consensus sequence [(T/C)CAAGG(T/C)C(A/G)]. By performing yeast one-hybrid assays, the ability of SmFTZ-F1alpha to bind productively to a p14-derived 9-base pair sequence was demonstrated in vivo. The ability of the full-length SmFTZ-F1alpha to transactivate reporter gene expression was shown to be A/B domain-dependent in a yeast system. In addition, the hinge region contained an unexpected activation function (AF) domain, termed AF-3, while no transactivation activity was detected within the E/F domain. This AF-3 region (from aa 982 to aa 1110) revealed a strong autonomous transactivation activity, which was masked when it was present in the full-length SmFTZ-F1alpha. Taken together, our results suggest that SmFTZ-F1alpha possesses the characteristic DNA binding specificity of FTZ-F1 subfamily members and the capacity to transactivate a reporter gene.
Mol Biochem Parasitol 2006 Nov
PMID:Characterization of the DNA-binding properties and the transactivation activity of Schistosoma mansoni nuclear receptor fushi tarazu-factor 1alpha (SmFTZ-F1alpha). 1689 Mar 3

Binding of 1alpha,25-dihydroxy Vitamin D3 to the C-terminal domain (LBD) of its receptor (VDR), induces a conformational change that enables interaction of VDR with transcriptional coactivators such as the members of the p160/SRC family or the DRIP (Vitamin D interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. Recent reports indicate that nuclear receptors, including VDR, interact with p160/SRC members and the DRIP/Mediator complex in a sequential, cyclical, and mutually exclusive manner when bound to a target promoter, exhibiting also a high exchange rate. Here, we present an overview of how these coactivators are recruited to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1alpha,25-dihydroxy Vitamin D3. We find that in intact osteoblastic cells VDR and SRC-1 rapidly bind to the OC promoter in response to the ligand. This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter. In contrast, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter after several hours of incubation with 1alpha,25-dihydroxy Vitamin D3. Together, our results indicate that VDR preferentially recruits SRC-1 to enhance basal bone-specific OC gene transcription. We propose a model where specific protein-DNA and protein-protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the VDR-SRC-1 complex.
J Steroid Biochem Mol Biol 2007 Mar
PMID:The 1alpha,25-dihydroxy Vitamin D3 receptor preferentially recruits the coactivator SRC-1 during up-regulation of the osteocalcin gene. 1721 95

Lafora disease (LD), an autosomal recessive neurodegenerative disorder, is characterized by the presence of cytoplasmic polyglucosan inclusions known as Lafora bodies in several tissues including the brain. Laforin, a protein phosphatase, and malin, an ubiquitin ligase, are two of the proteins that are known to be defective in LD. Malin interacts with laforin and promotes its polyubiquitination and degradation. Here we show that malin and laforin co-localize in endoplasmic reticulum (ER) and that they form centrosomal aggregates when treated with proteasomal inhibitors in both neuronal and non-neuronal cells. Laforin/malin aggregates co-localize with gamma-tubulin and cause redistribution of alpha-tubulin. These aggregates are also immunoreactive to ubiquitin, ubiquitin-conjugating enzyme, ER chaperone and proteasome subunits, demonstrating their aggresome-like properties. Furthermore, we show that the centrosomal aggregation of laforin and malin is dependent on the functional microtubule network. Laforin and malin form aggresome when expressed together or otherwise, suggesting that the two proteins are recruited to the centrosome independent of each other. Taken together, our results suggest that the centrosomal accumulation of malin, possibly with the help of laforin, may enhance the ubiquitination of its substrates and facilitate their efficient degradation by proteasome. Defects in malin or laforin may thus lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron. Thus, defects in protein degradation and clearance are likely to be the primary trigger in the physiopathology of LD.
Hum Mol Genet 2007 Apr 01
PMID:Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. 1733 85

Steroid hormone receptors (SRs) are transcription factors that act as regulatory switches by altering gene expression in response to ligands. The highly conserved ligand-binding domain of SRs is a precise but versatile molecular switch that can adopt distinct conformations. Differential stabilization of these conformations by ligands, DNA response elements and transcriptional coregulators controls the activity of SRs in a gene-specific and cell-specific manner. In the case of the glucocorticoid receptor (GR), high-affinity ligand binding requires the interaction of the LBD with the heat shock protein 90 (Hsp90). Here, we show that the dependence of the ligand binding ability of GR on Hsp90 can be modified by the replacement of single amino acids within an allosteric network that connects the buried ligand-binding pocket and a solvent-exposed coregulator interaction surface. Each of the identified mutations altered the equilibrium between alternative GR conformations distinctively, indicating that the Hsp90 dependence of SRs may correlate with differences in the conformational dynamics of these receptors. Our results suggest that Hsp90 stabilizes the GR ligand-binding pocket indirectly by utilizing the allosteric network, while allowing the receptor to remain structurally uncommitted. Thus, in addition to ensuring the accessibility of the GR ligand-binding pocket to ligands, Hsp90 seems to enable hormones and coregulators to act as allosteric effectors, which forms the basis for gene-specific and cell-specific responses of GR to ligands.
J Mol Biol 2007 May 04
PMID:A conformational switch in the ligand-binding domain regulates the dependence of the glucocorticoid receptor on Hsp90. 1736 9

Lafora progressive myoclonus epilepsy (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies. LD is caused by mutations in two genes, EPM2A and EPM2B, encoding respectively laforin, a dual-specificity protein phosphatase, and malin, an E3 ubiquitin ligase. Previously, we and others have suggested that the interactions between laforin and PTG (a regulatory subunit of type 1 protein phosphatase) and between laforin and malin are critical in the pathogenesis of LD. Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. Furthermore, we demonstrate that the interaction between laforin and malin is a regulated process that is modulated by the AMP-activated protein kinase (AMPK). These findings provide further insights into the critical role of the laforin-malin complex in the control of glycogen metabolism and unravel a novel link between the energy sensor AMPK and glycogen metabolism. These data advance our understanding of the functional role of laforin and malin, which hopefully will facilitate the development of appropriate LD therapies.
Hum Mol Genet 2008 Mar 01
PMID:Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. 1802 86

The EPM2A gene, encoding the dual-phosphatase laforin, is mutated in a fatal form of progressive myoclonus epilepsy known as Lafora disease (LD). The EPM2A gene, by differential splicing of its transcripts, is known to encode two laforin isoforms having distinct carboxyl termini; a major isoform localized in the cytoplasm (laf331), and a minor isoform that is targeted to the nucleus as well (laf317). We show here that the two laforin isoforms interact with each other and form homo and heterodimers. The homodimer of laf331 display robust phosphatase activity, whereas the laf317 homodimer and the laf331-laf317 heterodimer lack phosphatase activity. Laf331 binds to glycogen only as a monomeric form. Laf317, on the other hand, was unable to bind to glycogen as a homodimer or as a heterodimer. Similar to laf331, laf317 interacts with and functions as a substrate for the malin ubiquitin ligase--a product of another gene defective in LD. Malin, however, shows higher affinity towards laf331 when compared with laf317. We have also tested the effect of LD-associated mutations, whose effects are restricted to the laf331 isoform, on laf331-laf317 interaction. Two such mutations are known and both abolish the interactions between laf317 and laf331 and their heterodimerization, but not the homodimerization property of laf331. Thus, laf317 could function as a dominant-negative regulator of laf331, and laf331-specific mutations might affect laf317 functions as well. Thus, our findings reveal a novel mechanism for the EPM2A gene function, regulated by alternative splicing, in normal as well as disease conditions.
Hum Mol Genet 2008 Oct 01
PMID:Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy. 1861 30


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