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271.
Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1 总被引:26,自引:0,他引:26
Li YM Xu M Lai MT Huang Q Castro JL DiMuzio-Mower J Harrison T Lellis C Nadin A Neduvelil JG Register RB Sardana MK Shearman MS Smith AL Shi XP Yin KC Shafer JA Gardell SJ 《Nature》2000,405(6787):689-694
Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen. 相似文献
272.
Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean 总被引:30,自引:0,他引:30
Clapham JC Arch JR Chapman H Haynes A Lister C Moore GB Piercy V Carter SA Lehner I Smith SA Beeley LJ Godden RJ Herrity N Skehel M Changani KK Hockings PD Reid DG Squires SM Hatcher J Trail B Latcham J Rastan S Harper AJ Cadenas S Buckingham JA Brand MD Abuin A 《Nature》2000,406(6794):415-418
Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal. 相似文献
273.
Zusammenfassung Untersuchungen mit203Pb in vitro ergeben, dass Blei in den Erythrozyten vorwiegend an Hämoglobin gebunden wird, während Stromasubstanzen kein Blei aufnehmen. 相似文献
274.
Active transport in the rabbit blastocyst 总被引:1,自引:0,他引:1
M W Smith 《Experientia》1970,26(7):736-738
275.
Sliding-layer conformational change limited by the quaternary structure of plant RuBisCO 总被引:1,自引:0,他引:1
RuBisCO, D-ribulose-1,5-bisphosphate carboxylase-oxygenase (EC 4.1.1.39), converts carbon dioxide to sugar in the first step of photosynthesis. In plants and some bacteria, this enzyme has an L8S8 structure, where L is the large catalytic subunit and S is the small subunit of unknown function. The molecule resembles a keg 105 A along the 4-fold axis and 132 A in diameter at the widest point of the keg. Here we describe the quaternary structure of RuBisCO from N. tabacum, the first L8S8 type known from an X-ray crystallographic study at near-atomic resolution (3 A). The structure shows that all eight L subunits are elongated along the 4-fold axis so that the molecule cannot be simply described as layers of subunits, as it had been from studies by electron microscopy. The structure, with its elongated and interdigitated L subunits, is evidence against a large, sliding-layer conformational change in plant RuBisCO, as proposed recently in Nature for the same enzyme from Alcaligenes eutrophus. 相似文献
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Brassins--a new family of plant hormones from rape pollen 总被引:26,自引:0,他引:26