929 research outputs found
Automatically extracting functionally equivalent proteins from SwissProt
In summary, FOSTA provides an automated analysis of annotations in UniProtKB/Swiss-Prot to enable groups of proteins already annotated as functionally equivalent, to be extracted. Our results demonstrate that the vast majority of UniProtKB/Swiss-Prot functional annotations are of high quality, and that FOSTA can interpret annotations successfully. Where FOSTA is not successful, we are able to highlight inconsistencies in UniProtKB/Swiss-Prot annotation. Most of these would have presented equal difficulties for manual interpretation of annotations. We discuss limitations and possible future extensions to FOSTA, and recommend changes to the UniProtKB/Swiss-Prot format, which would facilitate text-mining of UniProtKB/Swiss-Prot
Scarring Effects on Tunneling in Chaotic Double-Well Potentials
The connection between scarring and tunneling in chaotic double-well
potentials is studied in detail through the distribution of level splittings.
The mean level splitting is found to have oscillations as a function of energy,
as expected if scarring plays a role in determining the size of the splittings,
and the spacing between peaks is observed to be periodic of period
{} in action. Moreover, the size of the oscillations is directly
correlated with the strength of scarring. These results are interpreted within
the theoretical framework of Creagh and Whelan. The semiclassical limit and
finite-{} effects are discussed, and connections are made with reaction
rates and resonance widths in metastable wells.Comment: 22 pages, including 11 figure
Influences of Excluded Volume of Molecules on Signaling Processes on Biomembrane
We investigate the influences of the excluded volume of molecules on
biochemical reaction processes on 2-dimensional surfaces using a model of
signal transduction processes on biomembranes. We perform simulations of the
2-dimensional cell-based model, which describes the reactions and diffusion of
the receptors, signaling proteins, target proteins, and crowders on the cell
membrane. The signaling proteins are activated by receptors, and these
activated signaling proteins activate target proteins that bind autonomously
from the cytoplasm to the membrane, and unbind from the membrane if activated.
If the target proteins bind frequently, the volume fraction of molecules on the
membrane becomes so large that the excluded volume of the molecules for the
reaction and diffusion dynamics cannot be negligible. We find that such
excluded volume effects of the molecules induce non-trivial variations of the
signal flow, defined as the activation frequency of target proteins, as
follows. With an increase in the binding rate of target proteins, the signal
flow varies by i) monotonically increasing; ii) increasing then decreasing in a
bell-shaped curve; or iii) increasing, decreasing, then increasing in an
S-shaped curve. We further demonstrate that the excluded volume of molecules
influences the hierarchical molecular distributions throughout the reaction
processes. In particular, when the system exhibits a large signal flow, the
signaling proteins tend to surround the receptors to form receptor-signaling
protein clusters, and the target proteins tend to become distributed around
such clusters. To explain these phenomena, we analyze the stochastic model of
the local motions of molecules around the receptor.Comment: 31 pages, 10 figure
Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR
Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches
Dose Precision Using a Pretransplant Test PK of Intravenous Busulfan Prior to BuCyVP-16 Preparative Regimen in Lymphoma
A mitochondrial half-size ABC transporter is involved in cadmium tolerance in Chlamydomonas reinhardtii
Five cadmium-sensitive insertional mutants, all affected at the CDS1 ('cadmium-sensitive 1') locus, have been previously isolated in the unicellular green alga Chlamydomonas reinhardtii. We here describe the cloning of the Cds1 gene (8314 bp with 26 introns) and the corresponding cDNA. The Cds1 gene, strongly induced by cadmium, encodes a putative protein (CrCds1) of 1062 amino acid residues that belongs to the ATM/HMT subfamily of half-size ABC transporters. This subfamily includes both vacuolar HMT-type proteins transporting phytochelatin-cadmium complexes from the cytoplasm to the vacuole and mitochondrial ATM-type proteins involved in the maturation of cytosolic Fe/S proteins. Unlike the Delta sphmt1 cadmium-sensitive mutant of Schizosaccharomyces pombe that lacks a vacuolar HMT-type transporter, the cds1 mutant accumulates a high amount of phytochelatin-cadmium complexes. By epitope tagging, the CrCds1 protein was localized in the mitochondria. Even though mitochondria of cds1 do not accumulate important amounts of 'free' iron, the mutant cells are hypersensitive to high iron concentrations. Our data show for the first time that a mitochondrial ATM-like transporter plays a major role in tolerance to cadmium.Peer reviewe
DNA helicase and helicase–nuclease enzymes with a conserved iron–sulfur cluster
Conserved Iron–Sulfur (Fe–S) clusters are found in a growing family of metalloproteins that are implicated in prokaryotic and eukaryotic DNA replication and repair. Among these are DNA helicase and helicase–nuclease enzymes that preserve chromosomal stability and are genetically linked to diseases characterized by DNA repair defects and/or a poor response to replication stress. Insight to the structural and functional importance of the conserved Fe–S domain in DNA helicases has been gleaned from structural studies of the purified proteins and characterization of Fe–S cluster site-directed mutants. In this review, we will provide a current perspective of what is known about the Fe–S cluster helicases, with an emphasis on how the conserved redox active domain may facilitate mechanistic aspects of helicase function. We will discuss testable models for how the conserved Fe–S cluster might operate in helicase and helicase–nuclease enzymes to conduct their specialized functions that help to preserve the integrity of the genome
Acetyltransferases and tumour suppression
The acetyltransferase p300 was first identified associated with the adenoviral transforming protein E1A, suggesting a potential role for p300 in the regulation of cell proliferation. Direct evidence demonstrating a role for p300 in human tumours was lacking until the recentl publication by Gayther et al, which strongly supports a role for p300 as a tumour suppressor. The authors identify truncating mutations associated with the loss or mutation of the second allele in both tumour samples and cell lines, suggesting that loss of p300 may play a role in the development of a subset of human cancers
Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort
INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals
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