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By admin, on February 22nd, 2012
J Biol Chem. 2012 Feb 17;
Zhao Y, Wang Y, Hu J, Zhang X, Zhang YW
Accumulation of the neurotoxic β-amyloid (Aβ) peptide in the brain is central to the pathogenesis of Alzheimer disease (AD). Aβ is derived from the β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases; and the production of Aβ is greatly affected by the subcellular localization of these factors. CUTA, the mammalian cutA divalent cation tolerance homolog (E.coli), has been proposed to mediate acetylcholinesterase activity and copper homeostasis which are important in AD pathology. However, the exact function of CUTA remains largely unclear. Here we show that human CUTA has several variants that differ in their amino- (N-) terminal length and are separated as heavy (H) and light (L) components. The H component has the longest N-terminus and is membrane-associated, whereas the L component is N-terminally truncated at various sites and localized in the cytosol. Importantly, we demonstrate that the H component of CUTA interacts through its N-terminus with the transmembrane domain of β-site APP cleaving enzyme 1 (BACE1), the putative β-secretase, mainly in the Golgi/trans-Golgi network (TGN). Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1-mediated APP processing/Aβ secretion, respectively. RNA interference of CUTA decelerates intracellular trafficking of BACE1 from the Golgi/TGN to the cell surface and reduces the steady-state level of cell surface BACE1. Our results identify the H component of CUTA as a novel BACE1-interacting protein that mediates the intracellular trafficking of BACE1 and the processing of APP to Aβ.
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CutA divalent cation tolerance homolog (E. coli) (CUTA) regulates β-cleavage of β-amyloid precursor protein (APP) through interacting with β-Site APP cleaving protein 1 (BACE1).
By admin, on February 21st, 2012
Plant Physiol. 2012 Feb 13;
Qi D, Deyoung BJ, Innes RW
The Arabidopsis RPS5 disease resistance protein mediates recognition of the Pseudomonas syringae effector protein AvrPphB. RPS5 belongs to the coiled-coil-nucleotide binding site-leucine-rich repeat (CC-NBS-LRR) family and is activated by AvrPphB-mediated cleavage of the protein kinase PBS1. Here we present a structure-function analysis of the CC and LRR domains of RPS5 using transient expression assays in Nicotiana benthamiana. We found that substituting the CC domain of RPS2 for the RPS5 CC domain did not alter RPS5 specificity and only moderately reduced its ability to activate programmed cell death, suggesting that the CC domain does not play a direct role in the recognition of PBS1 cleavage. Analysis of an RPS5-super Yellow Fluorescent Protein (sYFP) fusion revealed that RPS5 localizes to the plasma membrane (PM). Alanine substitutions of predicted myristoylation (glycine 2) and palmitoylation residues (cysteine 4) affected RPS5 PM localization, protein stability, and function in an additive manner, indicating that PM localization is essential to RPS5 function. The first 20 amino acids of RPS5 were sufficient for directing sYFP to the PM. C-terminal truncations of RPS5 revealed that the first 4 LRR repeats are sufficient for inhibiting RPS5 autoactivation; however, the complete LRR domain was required for recognition of PBS1 cleavage. Substitution of the RPS2 LRR domain resulted in autoactivation of RPS5, indicating that the LRR domain must co-evolve with the NBS domain. We conclude that the RPS5 LRR domain functions to suppress RPS5 activation in the absence of PBS1 cleavage, and promotes RPS5 activation in its presence.
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Structure-Function Analysis of the Coiled-Coil and Leucine-Rich Repeat Domains of the RPS5 Disease Resistance Protein.
By admin, on February 20th, 2012
Nihon Shinkei Seishin Yakurigaku Zasshi. 2011 Nov; 31(5-6): 195-9
Kasahara Y, Arime Y, Kubo Y, Fukui A, Sora I
Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD.
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[Neuronal development of the hyperdopaminergic animal model].
By admin, on February 20th, 2012
Nihon Shinkei Seishin Yakurigaku Zasshi. 2011 Nov; 31(5-6): 195-9
Kasahara Y, Arime Y, Kubo Y, Fukui A, Sora I
Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD.
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[Neuronal development of the hyperdopaminergic animal model].
By admin, on February 18th, 2012
Exp Cell Res . 2012 Feb 3; Robinson AJ, Kunji ER, Gross A Recent studies report mitochondrial carrier homolog 2 (MTCH2) as a novel and uncharacterized protein that acts as a receptor-like protein for the truncated BH3-interacting domain death agonist (tBID) protein in the outer membrane of mitochondria. These studies using mouse embryonic stem cells and fibroblasts, as well as mice with a conditional knockout of MTCH2 in the liver showed that deletion of MTCH2 hindered recruitment of tBID to the mitochondria with subsequent reductions in the activation of pro-apoptotic proteins, mitochondrial outer membrane permeabilization and apoptosis
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Mitochondrial carrier homolog 2 (MTCH2): The recruitment and evolution of a mitochondrial carrier protein to a critical player in apoptosis.
By admin, on February 17th, 2012
Objective: The endothelial or epithelial tight junctions (TJs) create a barrier to diffusion of solutes. It is suggested that the structure and function of the blood-brain barrier (BBB) have been damaged on the study of the …
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The Expression of Epithelial Membrane Protein 1 in the Blood-brain …
By admin, on February 17th, 2012
Objective: The endothelial or epithelial tight junctions (TJs) create a barrier to diffusion of solutes. It is suggested that the structure and function of the blood-brain barrier (BBB) have been damaged on the study of the …
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The Expression of Epithelial Membrane Protein 1 in the Blood-brain …
By admin, on February 16th, 2012
J Biol Chem. 2012 Feb 9;
Lefebvre B, Klaus-Heisen D, Pietraszewska-Bogiel A, Hervé C, Camut S, Auriac MC, Gasciolli V, Nurisso A, Gadella TW, Cullimore J
The lysin motif receptor like kinase, NFP, is a key protein in the legume Medicago truncatula for the perception of lipochitooligosaccharidic Nod Factors, which are secreted bacterial signals essential for establishing the nitrogen-fixing legume-rhizobia symbiosis. Predicted structural and genetic analyses strongly suggest that NFP is at least part of a Nod factor receptor, but few data are available about this protein. Characterization of a variant encoded by the mutant allele nfp-2 revealed the sensitivity of this protein to the endoplasmic reticulum quality control mechanisms, affecting its trafficking to the plasma membrane. Further analysis revealed that the extensive N-glycosylation of the protein is not essential for biological activity. In the NFP extracellular region, two CXC motifs and two other Cys residues were found to be involved in disulphide bridges and these are necessary for correct folding and localization of the protein. Analysis of the intracellular region revealed its importance for biological activity but suggests that it does not rely on kinase activity. This work shows that NFP trafficking to the plasma membrane is highly sensitive to regulation in the endoplasmic reticulum and has identified structural features of the protein, particularly disulphide bridges involving CXC motifs in the extracellular region that are required for its biological function.
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Role of N-glycosylation sites and CXC motifs in trafficking of Medicago trunculata Nod Factor Perception protein to the plasma membrane.
By admin, on February 15th, 2012
Optical platforms for assaying membrane protein function offer a promising route to scalable high-throughput screening (see picture). For the first time quantitative measurements of membrane protein inhibition are reported in …
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Quantification of Membrane Protein Inhibition by Optical Ion Flux in a …
By admin, on February 15th, 2012
Optical platforms for assaying membrane protein function offer a promising route to scalable high-throughput screening (see picture). For the first time quantitative measurements of membrane protein inhibition are reported in …
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Quantification of Membrane Protein Inhibition by Optical Ion Flux in a …
By admin, on February 13th, 2012
By admin, on February 13th, 2012
By admin, on February 13th, 2012
By admin, on February 6th, 2012
development and application of novel algorithms for the: * Protein biochemical function prediction * Proteome scale … by virtual ligand screening * Prediction of protein-protein, protein-DNA interactions and protein-RNA…
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Computational Systems Biology Postdoctoral Position in Methods Development at Skolnick Group, Center For the Study of Systems Biology, Georgia Institute of Technology (Atlanta, GA)
By admin, on February 6th, 2012
development and application of novel algorithms for the: * Protein biochemical function prediction * Proteome scale … by virtual ligand screening * Prediction of protein-protein, protein-DNA interactions and protein-RNA…
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Computational Systems Biology Postdoctoral Position in Methods Development at Skolnick Group, Center For the Study of Systems Biology, Georgia Institute of Technology (Atlanta, GA)
By admin, on February 6th, 2012
J Cell Sci. 2012 Feb 2;
McKinley RF, Yu CG, Harris TJ
Epithelial cell polarity is essential for animal development. The scaffold protein Bazooka (Baz/PAR-3) forms apical polarity landmarks to organize epithelial cells. However, it is unclear how Baz is recruited to the plasma membrane and how this is coupled with downstream effects. Baz contains an oligomerization domain, three PDZ domains, and binding regions for the protein kinase aPKC and phosphoinositide lipids. With a structure-function approach, we dissected the roles of these domains in the localization and function of Baz in the Drosophila embryonic ectoderm. We found that a multifaceted membrane association mechanism localizes Baz to the apical circumference. Although none of the Baz protein domains are essential for cortical localization, we determined that each contributes to cortical anchorage in a specific manner. We propose that the redundancies involved might provide plasticity and robustness to Baz polarity landmarks. We also identified specific downstream effects, including the promotion of epithelial structure, a positive-feedback loop that recruits aPKC, PAR-6 and Crumbs, and a negative-feedback loop that regulates Baz.
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Assembly of Bazooka polarity landmarks through a multifaceted membrane-association mechanism.
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