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排序方式: 共有755条查询结果,搜索用时 468 毫秒
751.
Xiao B Heath R Saiu P Leiper FC Leone P Jing C Walker PA Haire L Eccleston JF Davis CT Martin SR Carling D Gamblin SJ 《Nature》2007,449(7161):496-500
AMP-activated protein kinase (AMPK) regulates cellular metabolism in response to the availability of energy and is therefore a target for type II diabetes treatment. It senses changes in the ratio of AMP/ATP by binding both species in a competitive manner. Thus, increases in the concentration of AMP activate AMPK resulting in the phosphorylation and differential regulation of a series of downstream targets that control anabolic and catabolic pathways. We report here the crystal structure of the regulatory fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate groups of AMP/ATP lie in a groove on the surface of the gamma domain, which is lined with basic residues, many of which are associated with disease-causing mutations. Structural and solution studies reveal that two sites on the gamma domain bind either AMP or Mg.ATP, whereas a third site contains a tightly bound AMP that does not exchange. Our binding studies indicate that under physiological conditions AMPK mainly exists in its inactive form in complex with Mg.ATP, which is much more abundant than AMP. Our modelling studies suggest how changes in the concentration of AMP ([AMP]) enhance AMPK activity levels. The structure also suggests a mechanism for propagating AMP/ATP signalling whereby a phosphorylated residue from the alpha and/or beta subunits binds to the gamma subunit in the presence of AMP but not when ATP is bound. 相似文献
752.
Replicating genotype-phenotype associations 总被引:1,自引:0,他引:1
NCI-NHGRI Working Group on Replication in Association Studies Chanock SJ Manolio T Boehnke M Boerwinkle E Hunter DJ Thomas G Hirschhorn JN Abecasis G Altshuler D Bailey-Wilson JE Brooks LD Cardon LR Daly M Donnelly P Fraumeni JF Freimer NB Gerhard DS Gunter C Guttmacher AE Guyer MS Harris EL Hoh J Hoover R Kong CA Merikangas KR Morton CC Palmer LJ Phimister EG Rice JP Roberts J Rotimi C Tucker MA Vogan KJ Wacholder S Wijsman EM Winn DM Collins FS 《Nature》2007,447(7145):655-660
753.
Stream denitrification across biomes and its response to anthropogenic nitrate loading 总被引:11,自引:0,他引:11
Mulholland PJ Helton AM Poole GC Hall RO Hamilton SK Peterson BJ Tank JL Ashkenas LR Cooper LW Dahm CN Dodds WK Findlay SE Gregory SV Grimm NB Johnson SL McDowell WH Meyer JL Valett HM Webster JR Arango CP Beaulieu JJ Bernot MJ Burgin AJ Crenshaw CL Johnson LT Niederlehner BR O'Brien JM Potter JD Sheibley RW Sobota DJ Thomas SM 《Nature》2008,452(7184):202-205
Anthropogenic addition of bioavailable nitrogen to the biosphere is increasing and terrestrial ecosystems are becoming increasingly nitrogen-saturated, causing more bioavailable nitrogen to enter groundwater and surface waters. Large-scale nitrogen budgets show that an average of about 20-25 per cent of the nitrogen added to the biosphere is exported from rivers to the ocean or inland basins, indicating that substantial sinks for nitrogen must exist in the landscape. Streams and rivers may themselves be important sinks for bioavailable nitrogen owing to their hydrological connections with terrestrial systems, high rates of biological activity, and streambed sediment environments that favour microbial denitrification. Here we present data from nitrogen stable isotope tracer experiments across 72 streams and 8 regions representing several biomes. We show that total biotic uptake and denitrification of nitrate increase with stream nitrate concentration, but that the efficiency of biotic uptake and denitrification declines as concentration increases, reducing the proportion of in-stream nitrate that is removed from transport. Our data suggest that the total uptake of nitrate is related to ecosystem photosynthesis and that denitrification is related to ecosystem respiration. In addition, we use a stream network model to demonstrate that excess nitrate in streams elicits a disproportionate increase in the fraction of nitrate that is exported to receiving waters and reduces the relative role of small versus large streams as nitrate sinks. 相似文献
754.
d'Adda di Fagagna F Reaper PM Clay-Farrace L Fiegler H Carr P Von Zglinicki T Saretzki G Carter NP Jackson SP 《Nature》2003,426(6963):194-198
Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. 相似文献
755.