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191.
RNA recognition motifs (RRMs) constitute versatile macromolecular interaction platforms. They are found in many components of spliceosomes, in which they mediate RNA and protein interactions by diverse molecular strategies. The human U11/U12-65K protein of the minor spliceosome employs a C-terminal RRM to bind hairpin III of the U12 small nuclear RNA (snRNA). This interaction comprises one side of a molecular bridge between the U11 and U12 small nuclear ribonucleoprotein particles (snRNPs) and is reminiscent of the binding of the N-terminal RRMs in the major spliceosomal U1A and U2B″ proteins to hairpins in their cognate snRNAs. Here we show by mutagenesis and electrophoretic mobility shift assays that the β-sheet surface and a neighboring loop of 65K C-terminal RRM are involved in RNA binding, as previously seen in canonical RRMs like the N-terminal RRMs of the U1A and U2B″ proteins. However, unlike U1A and U2B″, some 30 residues N-terminal of the 65K C-terminal RRM core are additionally required for stable U12 snRNA binding. The crystal structure of the expanded 65K C-terminal RRM revealed that the N-terminal tail adopts an α-helical conformation and wraps around the protein toward the face opposite the RNA-binding platform. Point mutations in this part of the protein had only minor effects on RNA affinity. Removal of the N-terminal extension significantly decreased the thermal stability of the 65K C-terminal RRM. These results demonstrate that the 65K C-terminal RRM is augmented by an N-terminal element that confers stability to the domain, and thereby facilitates stable RNA binding. 相似文献
192.
David A. Hughes Anke Hinney Harald Brumm Anne-Kathrin Wermter Heike Biebermann Johannes Hebebrand Mark Stoneking 《Human genetics》2009,124(6):633-647
The melanocortin 4 receptor (MC4R) is routinely investigated for the role it plays in human obesity, as mutations in MC4R are the most common dominantly inherited form of the disease. As little is known about the evolutionary history of this locus,
we investigated patterns of variation at MC4R in a worldwide sample of 1,015 humans from 51 populations, and in 8 central chimpanzees. There is a significant paucity of
diversity at MC4R in humans, but not in chimpanzees. The spectrum of mutations in humans, combined with the overall low level of diversity,
suggests that most (if not all) of the observed non-synonymous polymorphisms are likely to be transient deleterious mutations.
The MC4R coding region was resequenced in 12 primate species and sequences from an additional 29 vertebrates were included in molecular
evolutionary analyses. MC4R is highly conserved throughout vertebrate evolution, and has apparently been subject to high levels of continuous purifying
selection that increased approximately threefold during primate evolution. Furthermore, the strong selection extends to codon
usage bias, where most silent mutations are expected to be either quickly fixed or removed from the population, which may
help explain the unusually low levels of silent polymorphisms in humans. Finally, there is a significant tendency for non-synonymous
mutations that impact MC4R function to occur preferentially at sites that are identified by evolutionary analyses as being subject to very strong purifying
selection. The information from this study should help inform future epidemiological investigations of MC4R.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
193.
The DEAD-box RNA-helicase Dbp5/Rat8 is known for its function in nuclear mRNA export, where it displaces the export receptor Mex67 from the mRNA at the cytoplasmic side of the nuclear pore complex (NPC). Here we show that Dbp5 is also required for the nuclear export of both pre-ribosomal subunits. Yeast temperature-sensitive dbp5 mutants accumulate both ribosomal particles in their nuclei. Furthermore, Dbp5 genetically and physically interacts with known ribosomal transport factors such as Nmd3. Similar to mRNA export we show that also for ribosomal transport Dbp5 is required at the cytoplasmic side of the NPC. However, unlike its role in mRNA export, Dbp5 does not seem to undergo its ATPase cycle for this function, as ATPase-deficient dbp5 mutants that selectively inhibit mRNA export do not affect ribosomal transport. Furthermore, mutants of GLE1, the ATPase stimulating factor of Dbp5, show no major ribosomal export defects. Consequently, while Dbp5 uses its ATPase cycle to displace the export receptor Mex67 from the translocated mRNAs, Mex67 remains bound to ribosomal subunits upon transit to the cytoplasm, where it is detectable on translating ribosomes. Therefore, we propose a model, in which Dbp5 supports ribosomal transport by capturing ribosomal subunits upon their cytoplasmic appearance at the NPC, possibly by binding export factors such as Mex67. Thus, our findings reveal that although different ribonucleoparticles, mRNAs and pre-ribosomal subunits, use shared export factors, they utilize different transport mechanisms. 相似文献
194.
Adaptive radiations in butterflies: evolutionary history of the genus Erebia (Nymphalidae: Satyrinae) 下载免费PDF全文
Carlos Peña Heike Witthauer Irena Klečková Zdeněk Fric Niklas Wahlberg 《Biological journal of the Linnean Society. Linnean Society of London》2015,116(2):449-467
We studied the speciose butterfly genus Erebia by reconstructing its phylogenetic relationships using parsimony and Bayesian approaches. We estimated times and rates of diversification for its lineages and employed a biogeographical analysis in order to reconstruct its evolutionary history. DNA sequence data from one mitochondrial gene and three nuclear genes were analyzed for a total of 74 species in Erebia. The estimated dates of origin and diversification for clades, in combination with a biogeographical analysis, suggest that the genus originated in Asian Russia and started its diversification process around 23 Myr. An important event was the dispersal of a lineage from Asia to Western Europe between 23 and 17 Myr, which allowed the radiation of most of species in the genus. The diversification pattern is consistent with a model of diversity limited by clade richness, which implies an early rapid diversification followed by deceleration due to a decrease in speciation. We argue that these characteristics of the evolutionary history of Erebia are consistent with a density‐dependent scenario, with species radiation limited by filling of niche space and reduced resources. We found that the Boeberia parmenio appears strongly supported in the genus Erebia and therefore we place Boeberia Prout, 1901 as a junior synonym of Erebia Dalman, 1816 ( syn. nov. ). 相似文献
195.
Melissa L. Thomas Katrin Becker Kirsti Abbott Heike Feldhaar 《Biological invasions》2010,12(3):677-687
Invasive species are one of the main reasons for the ongoing global loss of biodiversity. Anoplolepis gracilipes is an invasive ant that has recently received significant attention due to its negative effect on the native fauna and flora
of Christmas Island, Indian Ocean. This species has contributed to a drastic change in the structure of the Christmas Island
rainforest through its negative impact on the island’s endemic red land crab, the dominant consumer on the islands forest
floor. In this study, we investigate the population structure of A. gracilipes on Christmas Island in order to determine whether multiple introductions occurred on the island and how they correspond to
known infestations. We genotyped 578 individuals collected from 50 nests across the Island. We identify two distinct subgroups
in the population that represent two different supercolonies. These supercolonies are interspersed across the island, however
both nuclear (microsatellites) and mitochondrial markers strongly suggest that there is no gene flow between the two colonies.
Significant heterozygote excess within the entire sampling area, with all but one worker examined being heterozygous for all
seven microsatellite loci, suggests an unusual reproductive system in these ants. Our results are consistent with recent sociogenetic
findings in a population of A. gracilipes in Northern Borneo. 相似文献
196.
Schäfer I von Leitner EC Schön G Koller D Hansen H Kolonko T Kaduszkiewicz H Wegscheider K Glaeske G van den Bussche H 《PloS one》2010,5(12):e15941
Objective
Multimorbidity is a common problem in the elderly that is significantly associated with higher mortality, increased disability and functional decline. Information about interactions of chronic diseases can help to facilitate diagnosis, amend prevention and enhance the patients'' quality of life. The aim of this study was to increase the knowledge of specific processes of multimorbidity in an unselected elderly population by identifying patterns of statistically significantly associated comorbidity.Methods
Multimorbidity patterns were identified by exploratory tetrachoric factor analysis based on claims data of 63,104 males and 86,176 females in the age group 65+. Analyses were based on 46 diagnosis groups incorporating all ICD-10 diagnoses of chronic diseases with a prevalence ≥ 1%. Both genders were analyzed separately. Persons were assigned to multimorbidity patterns if they had at least three diagnosis groups with a factor loading of 0.25 on the corresponding pattern.Results
Three multimorbidity patterns were found: 1) cardiovascular/metabolic disorders [prevalence female: 30%; male: 39%], 2) anxiety/depression/somatoform disorders and pain [34%; 22%], and 3) neuropsychiatric disorders [6%; 0.8%]. The sampling adequacy was meritorious (Kaiser-Meyer-Olkin measure: 0.85 and 0.84, respectively) and the factors explained a large part of the variance (cumulative percent: 78% and 75%, respectively). The patterns were largely age-dependent and overlapped in a sizeable part of the population. Altogether 50% of female and 48% of male persons were assigned to at least one of the three multimorbidity patterns.Conclusion
This study shows that statistically significant co-occurrence of chronic diseases can be subsumed in three prevalent multimorbidity patterns if accounting for the fact that different multimorbidity patterns share some diagnosis groups, influence each other and overlap in a large part of the population. In recognizing the full complexity of multimorbidity we might improve our ability to predict needs and achieve possible benefits for elderly patients who suffer from multimorbidity. 相似文献197.
Kristina Vth Carsten Mattes John Reinhard Roberto Covino Heike Stumpf Gerhard Hummer Robert Ernst 《The Journal of cell biology》2021,220(8)
The ER is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for maintaining ER homeostasis. Aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR. How the distinct signals from lipid bilayer stress and unfolded proteins are processed by the conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine cross-linking experiments in native membranes to establish its transmembrane architecture in signaling-active clusters. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration independent of the primary cause for ER stress. This suggests that different forms of stress converge in a common, signaling-active transmembrane architecture of Ire1. 相似文献
198.
199.
Recently we investigated the influence of classical and emerging antibiotics on the proteome of Bacillus subtilis including in our studies actinonin, a potent novel inhibitor of peptide deformylase. The protein synthesis pattern under actinonin treatment changed so dramatically that a direct comparison to the control pattern was impossible. Dual channel imaging revealed that actinonin treatment caused the majority of newly synthesised proteins to accumulate in spots different from the ones usually observed, indicating a more acidic isoelectric point. Two strategies were used to investigate the nature of the charge shift. In the first place, protein patterns of a conditional peptide deformylase mutant under nonrepressing and repressing conditions were compared. Secondly, several protein pairs excised from two-dimensional (2-D) gels of the peptide deformylase mutant, exponentially growing untreated wild-type and the actinonin treated wild-type were investigated with matrix-assisted laser desorption/ionization and electrospray ionization (ESI) time of flight mass spectrometry (TOF MS) for the existence of N-terminal formylation. Under nonrepressing conditions the mutant protein pattern resembled that of the wild-type. The loss of peptide deformylase activity under repressing conditions led to the same pI shift observed for actinonin treatment in the wild-type. Quadrupole TOF-MS on 11 protein pairs proved that the remaining N-terminal formyl residue was indeed responsible for the charge shift. Eight of these protein pairs were also present on 2-D gels of exponentially growing B. subtilis, where the more acidic, still formylated protein species represented the smaller parts. 相似文献
200.
Nagashima K Shumway SD Sathyanarayanan S Chen AH Dolinski B Xu Y Keilhack H Nguyen T Wiznerowicz M Li L Lutterbach BA Chi A Paweletz C Allison T Yan Y Munshi SK Klippel A Kraus M Bobkova EV Deshmukh S Xu Z Mueller U Szewczak AA Pan BS Richon V Pollock R Blume-Jensen P Northrup A Andersen JN 《The Journal of biological chemistry》2011,286(8):6433-6448
Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems. 相似文献