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101.
It is generally accepted that ions interact directly with lipids in biological membranes. Decades of biophysical studies on
pure lipid bilayer systems have shown that only certain types of ions, most significantly large anions and multivalent cations,
can fundamentally alter the structure and dynamics of lipid bilayers. It has long been accepted that at physiological concentrations
NaCl ions do not alter the physical behavior or structure of bilayers composed solely of zwitterionic phosphatidylcholine
(PC) lipids. Recent X-ray scattering experiments have reaffirmed this dogma, showing that below 1 M concentration, NaCl does
not significantly alter bilayer structure. However, despite this history, there is an ongoing controversy within the molecular
dynamics (MD) simulation community regarding NaCl/PC interactions. In particular, the CHARMM and GROMOS force fields show
dramatically different behavior, including the effect on bilayer structure, surface potential, and the ability to form stable,
coordinated ion–lipid complexes. Here, using long-timescale, constant-pressure simulations under the newest version of the
CHARMM force field, we find that Na+ and Cl− associate with PC head groups in a POPC bilayer with approximately equal, though weak, affinity, and that the salt has a
negligible effect on bilayer structure, consistent with earlier CHARMM results and more recent X-ray data. The results suggest
that interpretation of simulations where lipids interact with charged groups of any sort, including charged proteins, must
be carefully scrutinized. 相似文献
102.
103.
Cruz-García C Murray AE Klappenbach JA Stewart V Tiedje JM 《Journal of bacteriology》2007,189(2):656-662
Anaerobic cultures of Shewanella oneidensis MR-1 grown with nitrate as the sole electron acceptor exhibited sequential reduction of nitrate to nitrite and then to ammonium. Little dinitrogen and nitrous oxide were detected, and no growth occurred on nitrous oxide. A mutant with the napA gene encoding periplasmic nitrate reductase deleted could not respire or assimilate nitrate and did not express nitrate reductase activity, confirming that the NapA enzyme is the sole nitrate reductase. Hence, S. oneidensis MR-1 conducts respiratory nitrate ammonification, also termed dissimilatory nitrate reduction to ammonium, but not respiratory denitrification. 相似文献
104.
Christopher C. Valley Donna J. Arndt-Jovin Narain Karedla Mara P. Steinkamp Alexey I. Chizhik William S. Hlavacek Bridget S. Wilson Keith A. Lidke Diane S. Lidke 《Molecular biology of the cell》2015,26(22):4087-4099
Mutations within the epidermal growth factor receptor (EGFR/erbB1/Her1) are often associated with tumorigenesis. In particular, a number of EGFR mutants that demonstrate ligand-independent signaling are common in non–small cell lung cancer (NSCLC), including kinase domain mutations L858R (also called L834R) and exon 19 deletions (e.g., ΔL747-P753insS), which collectively make up nearly 90% of mutations in NSCLC. The molecular mechanisms by which these mutations confer constitutive activity remain unresolved. Using multiple subdiffraction-limit imaging modalities, we reveal the altered receptor structure and interaction kinetics of NSCLC-associated EGFR mutants. We applied two-color single quantum dot tracking to quantify receptor dimerization kinetics on living cells and show that, in contrast to wild-type EGFR, mutants are capable of forming stable, ligand-independent dimers. Two-color superresolution localization microscopy confirmed ligand-independent aggregation of EGFR mutants. Live-cell Förster resonance energy transfer measurements revealed that the L858R kinase mutation alters ectodomain structure such that unliganded mutant EGFR adopts an extended, dimerization-competent conformation. Finally, mutation of the putative dimerization arm confirmed a critical role for ectodomain engagement in ligand-independent signaling. These data support a model in which dysregulated activity of NSCLC-associated kinase mutants is driven by coordinated interactions involving both the kinase and extracellular domains that lead to enhanced dimerization. 相似文献
105.
Shixuan Zhang Christine Kriza Sandra Schaller Peter L. Kolominsky-Rabas National Leading-Edge Cluster Medical Technologies ‘Medical Valley EMN’ 《PloS one》2015,10(5)
Background
Due to an ageing population and demographic changes worldwide, a higher prevalence of heart disease is forecasted, which causes an even higher demand for cardiac implants in future. The increasing high incidence of clinical adverse events attributed especially to high-risk medical devices has led an advocated change from many stakeholders. This holds especially true for devices like cardiac implants, with their high-risk nature and high complication rates associated with considerable mortality, due to their frequent use in older populations with frequent co-morbidities. To ensure patients’ safety, the objective of this study is to analyze different cardiac implants recall reasons and different recall systems, based on an overview of the recalls of cardiac implant medical devices in the last decade. On the basis of the results from this structured analysis, this study provides recommendations on how to avoid such recalls from a manufacturer perspective, as well as how to timely react to an adverse event from a post-surveillance system perspective.Methods and Findings
A systematic search of cardiac implant recalls information has been performed in the PubMed, ScienceDirect and Scopus databases, as well as data sources in regulatory authorities from 193 UN Member States. Data has been extracted for the years 2004-2014 with the following criteria applied: cardiac implant medical device recalls and reasons for recall, associated harm or risk to patients. From the data sources described above, eleven regulatory authorities and 103 recall reports have been included in this study. The largest cardiac implant categories include ICDs 40.8%, pacemakers 14.5% and stents 14.5%. Regarding the recall reasons, the majority of reports were related to device battery problems (33.0%) and incorrect therapy delivery (31.1%). From a total of 103 recall reports, five reported death and serious injuries. Our review highlights weaknesses in the current cardiac implant recall system, including data reporting and management issues and provides recommendations for the improvement of safety information and management.Conclusion
Due to the mortality associated with the nature of cardiac implants, the traceability and transparency of safety hazards information is crucial. By a structured analysis of recall reasons and their efficient management, important knowledge is gained to inform an effective safety-reporting system for monitoring the safety of cardiac implanted patients, ideally by building up cardiac implant registries worldwide in the future. 相似文献106.
The widely accepted model for tumor necrosis factor 1 (TNFR1) signaling is that ligand binding causes receptor trimerization, which triggers a reorganization of cytosolic domains and thus initiates intracellular signaling. This model of stoichiometrically driven receptor activation does not account for the occurrence of ligand independent signaling in overexpressed systems, nor does it explain the constitutive activity of the R92Q mutant associated with TRAPS. More recently, ligand binding has been shown to result in the formation of high molecular weight, oligomeric networks. Although the dimer, shown to be the preligand structure, is thought to remain present within ligand-receptor networks, it is unknown whether network formation or ligand-induced structural change to the dimer itself is the trigger for TNFR1 signaling. In the present study, we investigate the available crystal structures of TNFR1 to explore backbone dynamics and infer conformational transitions associated with ligand binding. Using normal-mode analysis, we characterize the dynamic coupling between the TNFR1 ligand binding and membrane proximal domains and suggest a mechanism for ligand-induced activation. Furthermore, our data are supported experimentally by FRET showing that the constitutively active R92Q mutant adopts an altered conformation compared to wild-type. Collectively, our results suggest that the signaling competent architecture is the receptor dimer and that ligand binding modifies domain mobilities intrinsic to the receptor structure, allowing it to sample a separate, active conformation mediated by network formation. 相似文献
107.
Probing conservation of HAMP linker structure and signal transduction mechanism through analysis of hybrid sensor kinases
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The HAMP linker, a predicted structural element observed in many sensor kinases and methyl-accepting chemotaxis proteins, transmits signals between sensory input modules and output modules. HAMP linkers are located immediately inside the cytoplasmic membrane and are predicted to form two short amphipathic alpha-helices (AS-1 and AS-2) joined by an unstructured connector. HAMP linkers are found in the Escherichia coli nitrate- and nitrite-responsive sensor kinases NarX and NarQ (which respond to ligand by increasing kinase activity) and the sensor kinase CpxA (which responds to ligand by decreasing kinase activity). We constructed a series of hybrids with fusion points throughout the HAMP linker, in which the sensory modules of NarX or NarQ are fused to the transmitter modules of NarX, NarQ, or CpxA. A hybrid of the NarX sensor module and the CpxA HAMP linker and transmitter module (NarX-CpxA-1) responded to nitrate by decreasing kinase activity, whereas a hybrid in which the HAMP linker of NarX was replaced by that of CpxA (NarX-CpxA-NarX-1) responded to nitrate by increasing kinase activity. However, sequence variations between HAMP linkers do not allow free exchange of HAMP linkers or their components. Certain deletions in the NarX HAMP linker resulted in characteristic abnormal responses to ligand; similar deletions in the NarQ and NarX-CpxA-1 HAMP linkers resulted in responses to ligand generally similar to those seen in NarX. We conclude that the structure and action of the HAMP linker are conserved and that the HAMP linker transmits a signal to the output domain that ligand is bound. 相似文献
108.
Behaviour of topological marker proteins targeted to the Tat protein transport pathway 总被引:6,自引:0,他引:6
Stanley NR Sargent F Buchanan G Shi J Stewart V Palmer T Berks BC 《Molecular microbiology》2002,43(4):1005-1021
The Escherichia coli Tat system mediates Sec-independent export of protein precursors bearing twin arginine signal peptides. Formate dehydrogenase-N is a three-subunit membrane-bound enzyme, in which localization of the FdnG subunit to the membrane is Tat dependent. FdnG was found in the periplasmic fraction of a mutant lacking the membrane anchor subunit FdnI, confirming that FdnG is located at the periplasmic face of the cytoplasmic membrane. However, the phenotypes of gene fusions between fdnG and the subcellular reporter genes phoA (encoding alkaline phosphatase) or lacZ (encoding beta-galactosidase) were the opposite of those expected for analogous fusions targeted to the Sec translocase. PhoA fusion experiments have previously been used to argue that the peripheral membrane DmsAB subunits of the Tat-dependent enzyme dimethyl sulphoxide reductase are located at the cytoplasmic face of the inner membrane. Biochemical data are presented that instead show DmsAB to be at the periplasmic side of the membrane. The behaviour of reporter proteins targeted to the Tat system was analysed in more detail. These data suggest that the Tat and Sec pathways differ in their ability to transport heterologous passenger proteins. They also suggest that caution should be observed when using subcellular reporter fusions to determine the topological organization of Tat-dependent membrane protein complexes. 相似文献
109.
Crustacean and cheliceratan hemocyanins (oxygen-transport proteins) and
insect hexamerins (storage proteins) are homologous gene products, although
the latter do not bind oxygen and do not possess the copper- binding
histidines present in the hemocyanins. An alignment of 19 amino acid
sequences of hemocyanin subunits and insect hexamerins was made, based on
the conservation of elements of secondary structure observed in X-ray
structures of two hemocyanin subunits. The alignment was analyzed using
parsimony and neighbor-joining methods. Results provide strong indications
for grouping together the sequences of the 2 crustacean hemocyanin
subunits, the 5 cheliceratan hemocyanin subunits, and the 12 insect
hexamerins. Within the insect clade, four methionine- rich proteins, four
arylphorins, and two juvenile hormone-suppressible proteins from
Lepidoptera, as well as two dipteran proteins, form four separate groups.
In the absence of an outgroup sequence, it is not possible to present
information about the ancestral state from which these proteins are
derived. Although this family of proteins clearly consists of homologous
gene products, there remain striking differences in gene organization and
site of biosynthesis of the proteins within the cell. Because studies on
18S and 12S rRNA sequences indicate a rather close relationship between
insects and crustaceans, we propose that hemocyanin is the ancestral
arthropod protein and that insect hexamerins lost their copper-binding
capability after divergence of the insects from the crustaceans.
相似文献
110.