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71.
Sascha Rehm Peter Trodler J��rgen Pleiss 《Protein science : a publication of the Protein Society》2010,19(11):2122-2130
In most lipases, a mobile lid covers the substrate binding site. In this closed structure, the lipase is assumed to be inactive. Upon activation of the lipase by contact with a hydrophobic solvent or at a hydrophobic interface, the lid opens. In its open structure, the substrate binding site is accessible and the lipase is active. The molecular mechanism of this interfacial activation was studied for three lipases (from Candida rugosa, Rhizomucor miehei, and Thermomyces lanuginosa) by multiple molecular dynamics simulations for 25 ns without applying restraints or external forces. As initial structures of the simulations, the closed and open structures of the lipases were used. Both the closed and the open structure were simulated in water and in an organic solvent, toluene. In simulations of the closed lipases in water, no conformational transition was observed. However, in three independent simulations of the closed lipases in toluene the lid gradually opened. Thus, pathways of the conformational transitions were investigated and possible kinetic bottlenecks were suggested. The open structures in toluene were stable, but in water the lid of all three lipases moved towards the closed structure and partially unfolded. Thus, in all three lipases opening and closing was driven by the solvent and independent of a bound substrate molecule. 相似文献
72.
Plastids of diatoms and related algae evolved by secondary endocytobiosis, the uptake of a eukaryotic alga into a eukaryotic
host cell and its subsequent reduction into an organelle. As a result diatom plastids are surrounded by four membranes. Protein
targeting of nucleus encoded plastid proteins across these membranes depends on N-terminal bipartite presequences consisting
of a signal and a transit peptide-like domain. Diatoms and cryptophytes share a conserved amino acid motif of unknown function
at the cleavage site of the signal peptides (ASAFAP), which is particularly important for successful plastid targeting. Screening
genomic databases we found that in rare cases the very conserved phenylalanine within the motif may be replaced by tryptophan,
tyrosine or leucine. To test such unusual presequences for functionality and to better understand the role of the motif and
putative receptor proteins involved in targeting, we constructed presequence:GFP fusion proteins with or without modifications
of the “ASAFAP”-motif and expressed them in the diatom Phaeodactylum tricornutum. In this comprehensive mutational analysis we found that only the aromatic amino acids phenylalanine, tryptophan, tyrosine
and the bulky amino acid leucine at the +1 position of the predicted signal peptidase cleavage site allow plastid import,
as expected from the sequence comparison of native plastid targeting presequences of P. tricornutum and the cryptophyte Guillardia theta. Deletions within the signal peptide domains also impaired plastid import, showing that the presence of F at the N-terminus
of the transit peptide together with a cleavable signal peptide is crucial for plastid import.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
A. Gruber and S. Vugrinec contributed equally to this work. 相似文献
73.
74.
Spira D Stypmann J Tobin DJ Petermann I Mayer C Hagemann S Vasiljeva O Günther T Schüle R Peters C Reinheckel T 《The Journal of biological chemistry》2007,282(51):37045-37052
Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy (DCM). To understand the role of Ctsl in the maintenance of regular heart morphology and function, it is critical to determine whether the DCM in Ctsl-/- mice is primarily because of the lack of Ctsl expression and activity in the cardiomyocytes or is caused by the additional extracardiac pathologies. Cardiomyocyte-specific expression of Ctsl in Ctsl-/- mice, using an alpha-myosin heavy chain promoter-Ctsl transgene, results in improved cardiac contraction, normal mRNA expression of atrionatriuretic peptide, normal heart weight, and regular ultrastructure of cardiomyocytes. Epithelial expression of cathepsin L2 (CTSL2) by a K14 promoter-CTSL2-transgene resulted in rescue of the Ctsl-/- hair loss phenotype. In these mice, cardiac atrionatriuretic peptide expression and end systolic heart dimensions were also significantly attenuated. However, cardiac contraction was not improved, and increased heart weight as well as the typical changes in lysosomal ultrastructure of Ctsl-/- hearts persisted. Myocardial fibrosis was detected in all Ctsl-/- mice irrespective of transgene-mediated cardiac Ctsl expression or extracardiac CTSL2 expression. Expression of collagen 1 was not enhanced in Ctsl-/- hearts, but a reduced collagenolytic activity suggests a role for Ctsl in collagen turnover by cardiac fibroblasts. We conclude that the DCM of Ctsl-/- mice is primarily caused by absence of the protease in cardiomyocytes, whereas the complex gross phenotype of Ctsl-deficient mice, i.e. the fur defect, results in additional stress to the heart. 相似文献
75.
Sexual differences in habitat preferences have been reported from a variety of animal taxa. However, the ultimate causes for
this intersexual niche segregation remain poorly understood. It has been suggested that sexual dimorphism is a consequence
of dimorphic niches based upon different reproductive costs and activities of the sexes. Here we provide evidence from field
data to examine this hypothesis by studying the behavioral background of niche segregation in Tetrix ceperoi. Our data revealed distinct sexual differences in the substrates on which the insects perched and in the solar radiation
of these locations. Males were found at brighter locations and more often on bare ground than females. Incorporation of behavioral
data in our analysis showed that patches of bare ground were mainly utilized during mating behavior, in which males invested
more time than females. In contrast, females spent more time resting and feeding in the vegetation. Intersexual differences
in the proportion of autotomized individuals indicate that males might suffer higher predation risks. These patterns support
the dimorphic niches hypothesis, which suggests that differential habitat utilization is caused by differences in the life
history strategies of males and females, since males should accept a higher predation risk due to the benefits of multiple
matings. Females should invest more time in gaining nutrients and energy for egg production and survival, whereas males should
spend more time with searching for mates. We suggest that behavioral covariates should more often be implemented in ecological
analyses, since these might have a strong explanatory power. 相似文献
76.
Poly(ADP-ribosyl)ation in mammalian ageing 总被引:2,自引:0,他引:2
Poly(ADP-ribose) polymerases (PARPs) catalyze the post-translational modification of proteins with poly(ADP-ribose). Two PARP isoforms, PARP-1 and PARP-2, display catalytic activity by contact with DNA-strand breaks and are involved in DNA base-excision repair and other repair pathways. A body of correlative data suggests a link between DNA damage-induced poly(ADP-ribosyl)ation and mammalian longevity. Recent research on PARPs and poly(ADP-ribose) yielded several candidate mechanisms through which poly(ADP-ribosyl)ation might act as a factor that limits the rate of ageing. 相似文献
77.
Czirr E Leuchtenberger S Dorner-Ciossek C Schneider A Jucker M Koo EH Pietrzik CU Baumann K Weggen S 《The Journal of biological chemistry》2007,282(34):24504-24513
Abeta42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) constitute the founding members of a new class of gamma-secretase modulators that avoid side effects of pan-gamma-secretase inhibitors on NOTCH processing and function, holding promise as potential disease-modifying agents for Alzheimer disease (AD). These modulators are active in cell-free gamma-secretase assays indicating that they directly target the gamma-secretase complex. Additional support for this hypothesis was provided by the observation that certain mutations in presenilin-1 (PS1) associated with early-onset familial AD (FAD) change the cellular drug response to Abeta42-lowering NSAIDs. Of particular interest is the PS1-DeltaExon9 mutation, which provokes a pathogenic increase in the Abeta42/Abeta40 ratio and dramatically reduces the cellular response to the Abeta42-lowering NSAID sulindac sulfide. This FAD PS1 mutant is unusual as a splice-site mutation results in deletion of amino acids Thr(291)-Ser(319) including the endoproteolytic cleavage site of PS1, and an additional amino acid exchange (S290C) at the exon 8/10 splice junction. By genetic dissection of the PS1-DeltaExon9 mutation, we now demonstrate that a synergistic effect of the S290C mutation and the lack of endoproteolytic cleavage is sufficient to elevate the Abeta42/Abeta40 ratio and that the attenuated response to sulindac sulfide results partially from the deficiency in endoproteolysis. Importantly, a wider screen revealed that a diminished response to Abeta42-lowering NSAIDs is common among aggressive FAD PS1 mutations. Surprisingly, these mutations were also partially unresponsive to gamma-secretase inhibitors of different structural classes. This was confirmed in a mouse model with transgenic expression of the PS1-L166P mutation, in which the potent gamma-secretase inhibitor LY-411575 failed to reduce brain levels of soluble Abeta42. In summary, these findings highlight the importance of genetic background in drug discovery efforts aimed at gamma-secretase, suggesting that certain AD mouse models harboring aggressive PS mutations may not be informative in assessing in vivo effects of gamma-secretase modulators and inhibitors. 相似文献
78.
79.
Molecular modelling and synthetic arguments are valuable tools for the design of potential immunosuppressant agents. In this paper, eight proline-based compounds related to the AP1867 structure are studied and at least one of them is found to be a structurally good candidate for the inhibition of FKBP protein. Theoretical calculations were carried out to locate the most energetically favorable chemical substituent group relative to a core skeleton group on interaction with the FKBP binding cavity. Connolly accessible surface calculations have complemented the molecular mechanics and dynamics approaches. Calculated results were also analyzed on the basis of hydrogen bond interactions, relative energies of interaction, root-mean square deviations of amino acid residues of the crystallized protein, and orientation of the substituent groups within the active site. The results show a significant reduction in the relative interaction energies and very good shape complementarities between our final analog compound and the FKBP binding pocket. 相似文献
80.
Schunck Fabio Rodrigues Kleber Evangelista da Silva Marco Aurélio Galvão Prates Cristine Albano Ciro Piacentini Vítor Q. 《Acta ethologica》2022,25(3):135-140
acta ethologica - The Brazilian ruby, Heliodoxa rubricauda, is a forest species of hummingbird endemic to the Atlantic Forest. It belongs to an Andean clade of birds with robust and strong legs and... 相似文献