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281.
Opposite thermosensor in fruitfly and mouse 总被引:1,自引:0,他引:1
Viswanath V Story GM Peier AM Petrus MJ Lee VM Hwang SW Patapoutian A Jegla T 《Nature》2003,423(6942):822-823
282.
Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease. 相似文献
283.
X-ray structure of a voltage-dependent K+ channel 总被引:24,自引:0,他引:24
Voltage-dependent K+ channels are members of the family of voltage-dependent cation (K+, Na+ and Ca2+) channels that open and allow ion conduction in response to changes in cell membrane voltage. This form of gating underlies the generation of nerve and muscle action potentials, among other processes. Here we present the structure of KvAP, a voltage-dependent K+ channel from Aeropyrum pernix. We have determined a crystal structure of the full-length channel at a resolution of 3.2 A, and of the isolated voltage-sensor domain at 1.9 A, both in complex with monoclonal Fab fragments. The channel contains a central ion-conduction pore surrounded by voltage sensors, which form what we call 'voltage-sensor paddles'-hydrophobic, cationic, helix-turn-helix structures on the channel's outer perimeter. Flexible hinges suggest that the voltage-sensor paddles move in response to membrane voltage changes, carrying their positive charge across the membrane. 相似文献
284.
285.
Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes 总被引:1,自引:0,他引:1
Alvarez-Dolado M Pardal R Garcia-Verdugo JM Fike JR Lee HO Pfeffer K Lois C Morrison SJ Alvarez-Buylla A 《Nature》2003,425(6961):968-973
Recent studies have suggested that bone marrow cells possess a broad differentiation potential, being able to form new liver cells, cardiomyocytes and neurons. Several groups have attributed this apparent plasticity to 'transdifferentiation'. Others, however, have suggested that cell fusion could explain these results. Using a simple method based on Cre/lox recombination to detect cell fusion events, we demonstrate that bone-marrow-derived cells (BMDCs) fuse spontaneously with neural progenitors in vitro. Furthermore, bone marrow transplantation demonstrates that BMDCs fuse in vivo with hepatocytes in liver, Purkinje neurons in the brain and cardiac muscle in the heart, resulting in the formation of multinucleated cells. No evidence of transdifferentiation without fusion was observed in these tissues. These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types. 相似文献
286.
287.
Williamson IM Alvis SJ East JM Lee AG 《Cellular and molecular life sciences : CMLS》2003,60(8):1581-1590
The crystal structure of the K+ channel KcsA explains many features of ion channel function. The selectivity filter corresponds to a narrow region about 12 Å long and 3 Å wide, lined by carbonyl groups of the peptide backbone, through which a K+ ion can only move in a dehydrated form. The selectivity filter opens into a central, water-filled cavity leading to a gating site on the intracellular side of the channel. The channel is tetrameric, each monomer containing two transmembrane a helices, M1 and M2. Helix M1 faces the lipid bilayer and helix M2 faces the central channel pore; the M2 helices participate in subunit-subunit interactions. Helices M1 and M2 in each subunit pack as a pair of antiparallel coils with a heptad repeat, but the M2 helices of neighbouring subunits show fewer interactions, crossing at an angle of about –40°. Trp residues at the ends of the transmembrane helices form clear girdles on the two faces of the membrane, which, together with girdles of charged residues, define a hydrophobic thickness of about 37 Å for the channel. Binding constants for phosphatidylcholines to KcsA vary with fatty acyl chain length, the optimum chain length being C22. A phosphatidylcholine with this chain length gives a bilayer of thickness about 34 Å in the liquid crystalline phase, matching the hydrophobic thickness of the protein. However, a typical biological membrane has a hydrophobic thickness of about 27 Å. Thus either the transmembrane a helices of KcsA are more tilted in the native membrane than they are in the crystal structure, or the channel is under stress in the native membrane. The efficiency of hydrophobic matching between KcsA and the surrounding lipid bilayer is high over the chain length range C10–C24. The channel requires the presence of some anionic lipids for function, and fluorescence quenching studies show the presence of two classes of lipid binding site on KcsA; at one class of site (nonannular sites) anionic phospholipids bind more strongly than phosphatidylcholine, whereas at the other class of site (annular sites) phosphatidylcholines and anionic phospholipids bind with equal affinity. 相似文献
288.
Yang SJ Huh JW Lee JE Choi SY Kim TU Cho SW 《Cellular and molecular life sciences : CMLS》2003,60(11):2538-2546
Aluminum inactivated glutamate dehydrogenase (GDH) by a pseudo-first-order reaction at micromolar concentrations. A double-reciprocal plot gave a straight line with a kinact of 2.7 min-1 and indicated the presence of a binding step prior to inactivation. The inactivation was strictly pH dependent and a marked increase in sensitivity to aluminum was observed as the pH decreased. At a pH higher than 8.5, no inactivation was observed. The completely inactivated GDH contained 2 mol of aluminum per mole of enzyme subunit monomer. When preincubated with enzyme, several chelators such as citrate, NaF, N-(2-hydroxyethyl) ethylenediaminetriacetic acid or ethylenediaminetriacetic acid efficiently protected the enzyme against the aluminum inactivation. In a related experiment, only citrate and NaF released the aluminum from the completely inactivated aluminum-enzyme complex and fully recovered the enzyme activity. Ferritin, NADP+, or nerve growth factor did not show any effects on the recovery of the aluminum-inactivated GDH activity. The dissociation constant for the aluminum-enzyme complex was calculated to be 5.3 M. Although aluminum has been known to form a complex with nucleotides, no such effects were observed in the inactivation of GDH by aluminum as determined using GDHs mutated at the ADP-binding site, NAD+-binding site or GTP-binding site. Circular dichroism studies showed that the binding of aluminum to the enzyme induced a decrease in helices and sheets and an increase in random coil. Therefore, inactivation of GDH by aluminum is suggested to be due to the conformational change induced by aluminum binding. These results suggest a possibility that aluminum-induced alterations in enzymes of the glutamate system may be one of the causes of aluminum-induced neurotoxicity.Received 25 July 2003; received after revision 27 August 2003; accepted 15 September 2003 相似文献
289.
Crystal structure of parallel quadruplexes from human telomeric DNA 总被引:55,自引:0,他引:55
Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell from recombination and degradation. Disruption of telomere maintenance leads to eventual cell death, which can be exploited for therapeutic intervention in cancer. Telomeric DNA sequences can form four-stranded (quadruplex) structures, which may be involved in the structure of telomere ends. Here we describe the crystal structure of a quadruplex formed from four consecutive human telomeric DNA repeats and grown at a K(+) concentration that approximates its intracellular concentration. K(+) ions are observed in the structure. The folding and appearance of the DNA in this intramolecular quadruplex is fundamentally different from the published Na(+)-containing quadruplex structures. All four DNA strands are parallel, with the three linking trinucleotide loops positioned on the exterior of the quadruplex core, in a propeller-like arrangement. The adenine in each TTA linking trinucleotide loop is swung back so that it intercalates between the two thymines. This DNA structure suggests a straightforward path for telomere folding and unfolding, as well as ways in which it can recognize telomere-associated proteins. 相似文献
290.
Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus 总被引:19,自引:0,他引:19
Cheng MY Bullock CM Li C Lee AG Bermak JC Belluzzi J Weaver DR Leslie FM Zhou QY 《Nature》2002,417(6887):405-410