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Among the many surprises to arise from studies of prion biology, perhaps the most unexpected is the strain phenomenon whereby a single protein can misfold into structurally distinct, infectious states that cause distinguishable phenotypes. Similarly, proteins can adopt a spectrum of conformations in non-infectious diseases of protein folding; some are toxic and others are well tolerated. However, our understanding of the structural differences underlying prion strains and how these differences alter their physiological impact remains limited. Here we use a combination of solution NMR, amide hydrogen/deuterium (H/D) exchange and mutagenesis to study the structural differences between two strain conformations, termed Sc4 and Sc37 (ref. 5), of the yeast Sup35 prion. We find that these two strains have an overlapping amyloid core spanning most of the Gln/Asn-rich first 40 amino acids that is highly protected from H/D exchange and very sensitive to mutation. These features indicate that the cores are composed of tightly packed beta-sheets possibly resembling 'steric zipper' structures revealed by X-ray crystallography of Sup35-derived peptides. The stable structure is greatly expanded in the Sc37 conformation to encompass the first 70 amino acids, revealing why this strain shows increased fibre stability and decreased ability to undergo chaperone-mediated replication. Our findings establish that prion strains involve large-scale conformational differences and provide a structural basis for understanding a broad range of functional studies, including how conformational changes alter the physiological impact of prion strains. 相似文献
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"Disfacilitation" of red nucleus neurones 总被引:1,自引:0,他引:1
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A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids. 相似文献
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N. Tsukahara K. Toyama K. Kosaka M. Udo 《Cellular and molecular life sciences : CMLS》1965,21(9):544-545
Résumé Dans les neurones du noyau rouge, il a été demontré par l'enregistrement intracellulaire que les potentiels hyperpolarisants de longue durée sont produits par la stimulation de la région du noyau interposé et du cortex cérébelleux. En changeant le potentiel de membrane de la cellule, l'amplitude de l'hyperpolarisation diminue ou augmente parallèlement avec celle du potentiel postsynaptique excitateur (EPSP). En conséquence, l'hyperpolarisation ne provient pas du potentiel postsynaptique inhibiteur (IPSP), mais d'une réduction de l'effet tonique facilitateur exercé par le noyan interposé sur les neurones du noyau rouge («disfacilitation»). 相似文献
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Kodama R Norreys PA Mima K Dangor AE Evans RG Fujita H Kitagawa Y Krushelnick K Miyakoshi T Miyanaga N Norimatsu T Rose SJ Shozaki T Shigemori K Sunahara A Tampo M Tanaka KA Toyama Y Yamanaka T Zepf M 《Nature》2001,412(6849):798-802
Modern high-power lasers can generate extreme states of matter that are relevant to astrophysics, equation-of-state studies and fusion energy research. Laser-driven implosions of spherical polymer shells have, for example, achieved an increase in density of 1,000 times relative to the solid state. These densities are large enough to enable controlled fusion, but to achieve energy gain a small volume of compressed fuel (known as the 'spark') must be heated to temperatures of about 108 K (corresponding to thermal energies in excess of 10 keV). In the conventional approach to controlled fusion, the spark is both produced and heated by accurately timed shock waves, but this process requires both precise implosion symmetry and a very large drive energy. In principle, these requirements can be significantly relaxed by performing the compression and fast heating separately; however, this 'fast ignitor' approach also suffers drawbacks, such as propagation losses and deflection of the ultra-intense laser pulse by the plasma surrounding the compressed fuel. Here we employ a new compression geometry that eliminates these problems; we combine production of compressed matter in a laser-driven implosion with picosecond-fast heating by a laser pulse timed to coincide with the peak compression. Our approach therefore permits efficient compression and heating to be carried out simultaneously, providing a route to efficient fusion energy production. 相似文献
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A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease 总被引:16,自引:0,他引:16
Seki S Kawaguchi Y Chiba K Mikami Y Kizawa H Oya T Mio F Mori M Miyamoto Y Masuda I Tsunoda T Kamata M Kubo T Toyama Y Kimura T Nakamura Y Ikegawa S 《Nature genetics》2005,37(6):607-612
Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, LDD has strong genetic determinants. Using a case-control association study, we identified a functional SNP (1184T --> C, resulting in the amino acid substitution I395T) in CILP, which encodes the cartilage intermediate layer protein, that acts as a modulator of LDD susceptibility. CILP was expressed abundantly in intervertebral discs, and its expression increased as disc degeneration progressed. CILP colocalized with TGF-beta1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-beta1-mediated induction of cartilage matrix genes through direct interaction with TGF-beta1 and inhibition of TGF-beta1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-beta1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-beta signaling and that this regulation has a crucial role in the etiology and pathogenesis of LDD. Our study also adds to the list of connective tissue diseases that are associated with TGF-beta. 相似文献
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Résumé Chez le chat anesthésié au Nembutal ou au chloralose, les réponses évoquées dans les neurones du noyau rouge par les stimulations antidromiques et orthodromiques ont été étudiées au moyen de microélectrodes intracellulaires. 相似文献
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