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排序方式: 共有174条查询结果,搜索用时 31 毫秒
41.
Christopher A. Waudby Tuomas P.J. Knowles Jeremy N. Skepper John A. Carver John Christodoulou Sarah Meehan 《Biophysical journal》2010,98(5):843-851
αB-Crystallin is a small heat-shock protein (sHsp) that is colocalized with α-synuclein (αSyn) in Lewy bodies—the pathological hallmarks of Parkinson's disease—and is an inhibitor of αSyn amyloid fibril formation in an ATP-independent manner in vitro. We have investigated the mechanism underlying the inhibitory action of sHsps, and here we establish, by means of a variety of biophysical techniques including immunogold labeling and nuclear magnetic resonance spectroscopy, that αB-crystallin interacts with αSyn, binding along the length of mature amyloid fibrils. By measurement of seeded fibril elongation kinetics, both in solution and on a surface using a quartz crystal microbalance, this binding is shown to strongly inhibit further growth of the fibrils. The binding is also demonstrated to shift the monomer-fibril equilibrium in favor of dissociation. We believe that this mechanism, by which a sHsp interacts with mature amyloid fibrils, could represent an additional and potentially generic means by which at least some chaperones protect against amyloid aggregation and limit the onset of misfolding diseases. 相似文献
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Michael S. Christodoulou Sandra Liekens Konstantinos M. Kasiotis Serkos A. Haroutounian 《Bioorganic & medicinal chemistry》2010,18(12):4338-4350
The synthesis of a series of novel trisubstituted pyrazole derivatives and their PIFA-mediated conversion to molecules bearing the fused pyrazolo[4,3-c]quinoline ring system is reported. The anti-angiogenic activity of these compounds was evaluated by using in vitro assays for endothelial cell proliferation and migration, and in the chicken chorioallantoic membrane (CAM) assay. Compounds containing the fused pyrazolo[4,3-c]quinoline motifs emerged as potent anti-angiogenic compounds, which also had the ability to inhibit the growth of human breast (MCF-7) and cervical (Hela) carcinoma cells in vitro. 相似文献
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Christodoulou J Malmendal A Harper JF Chazin WJ 《The Journal of biological chemistry》2004,279(28):29092-29100
Calcium-dependent protein kinases (CDPKs) are structurally unique Ser/Thr kinases found in plants and certain protozoa. They are distinguished by a calmodulin-like regulatory apparatus (calmodulin-like domain (CaM-LD)) that is joined via a junction (J) region to the C-terminal end of the kinase catalytic domain. Like CaM, the CaM-LD is composed of two globular EF structural domains (N-lobe, C-lobe), each containing a pair of Ca(2+) binding sites. Spectroscopic analysis shows that the CaM-LD is comprised of helical elements, but the isolated CaM-LD does not form a conformationally homogeneous tertiary structure in the absence of Ca(2+). The addition of substoichiometric amounts of Ca(2+) is sufficient to stabilize the C-terminal lobe in a construct containing J and CaM-LD (JC) but not in the CaM-LD alone. Moreover, as J is titrated into Ca(2+)-saturated CaM-LD, interactions are stronger with the C-lobe than the N-lobe of the CaM-LD. Measurements of Ca(2+) affinity for JC reveal two cooperatively interacting high affinity binding sites (K(d)(,mean) = 5.6 nm at 20 mm KCl) in the C-lobe and two weaker sites in the N-lobe (K(d,mean) = 110 nm at 20 mm KCl). The corresponding Ca(2+) binding constants in the isolated CaM-LD are lower by more than 2 orders of magnitude, which indicates that the J region has an essential role in stabilizing the structure of the CDPK regulatory apparatus. The large differential affinity between the two domains together with previous studies on a plasmodium CDPK (Zhao, Y., Pokutta, S., Maurer, P., Lindt, M., Franklin, R. M., and Kappes, B. (1994) Biochemistry 33, 3714-3721) suggests a model whereby even at normally low cytosolic levels of Ca(2+), the C-lobe interacts with the junction, but the kinase remains in an autoinhibited state. Activation then occurs when Ca(2+) levels rise to fill the two weaker affinity binding sites in the N-lobe, thereby triggering a conformational change that leads to release of the autoinhibitory region. 相似文献
46.
Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation 总被引:5,自引:0,他引:5
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Weaving LS Christodoulou J Williamson SL Friend KL McKenzie OL Archer H Evans J Clarke A Pelka GJ Tam PP Watson C Lahooti H Ellaway CJ Bennetts B Leonard H Gécz J 《American journal of human genetics》2004,75(6):1079-1093
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations. 相似文献
47.
Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V 总被引:15,自引:0,他引:15
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Antonellis A Ellsworth RE Sambuughin N Puls I Abel A Lee-Lin SQ Jordanova A Kremensky I Christodoulou K Middleton LT Sivakumar K Ionasescu V Funalot B Vance JM Goldfarb LG Fischbeck KH Green ED 《American journal of human genetics》2003,72(5):1293-1299
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the first example of an aminoacyl tRNA synthetase being implicated in a human genetic disease, which makes genes that encode these enzymes relevant candidates for other inherited neuropathies and motor neuron diseases. 相似文献
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49.
Dedmon MM Christodoulou J Wilson MR Dobson CM 《The Journal of biological chemistry》2005,280(15):14733-14740
Parkinson's disease (PD) is a neurodegenerative disorder affecting an estimated 4 million people worldwide. Intracellular proteinaceous inclusions called Lewy bodies are the histological hallmarks of PD and are primarily composed of aggregated alpha-synuclein (alphaSyn). Although the detailed mechanisms remain unclear, mounting evidence suggests that the misfolding of alphaSyn into prefibrillar and fibrillar species is the driving force responsible for cellular toxicity. We show here that the molecular chaperone heat shock protein (Hsp) 70 strongly inhibits alphaSyn fibril formation via preferential binding to prefibrillar species. Moreover, our studies reveal that Hsp70 alters the characteristics of toxic alphaSyn aggregates and indicate that cellular toxicity arises from the prefibrillar forms of alphaSyn. This work therefore elucidates a specific role of Hsp70 in the pathogenesis of PD and supports the general concept that chaperone action is a crucial aspect in protecting against the otherwise damaging consequences of protein misfolding. 相似文献
50.
George Papaxoinis Vassiliki Kotoula Zoi Alexopoulou Konstantine T. Kalogeras Flora Zagouri Eleni Timotheadou Helen Gogas George Pentheroudakis Christos Christodoulou Angelos Koutras Dimitrios Bafaloukos Gerasimos Aravantinos Pavlos Papakostas Elpida Charalambous Kyriaki Papadopoulou Ioannis Varthalitis Ioannis Efstratiou Thomas Zaramboukas Helen Patsea Chrisoula D. Scopa Maria Skondra Paris Kosmidis Dimitrios Pectasides George Fountzilas 《PloS one》2015,10(10)