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1.
Roberto?H?Higa Roberto?C?Togawa Arnaldo?J?Montagner Juliana?CF?Palandrani Igor?KS?Okimoto Paula?R?Kuser Michel?EB?Yamagishi Adauto?L?Mancini Goran?NeshichEmail author 《BMC bioinformatics》2004,5(1):107
Background
The integration of many aspects of protein/DNA structure analysis is an important requirement for software products in general area of structural bioinformatics. In fact, there are too few software packages on the internet which can be described as successful in this respect. We might say that what is still missing is publicly available, web based software for interactive analysis of the sequence/structure/function of proteins and their complexes with DNA and ligands. Some of existing software packages do have certain level of integration and do offer analysis of several structure related parameters, however not to the extent generally demanded by a user. 相似文献2.
Bevan KS Chung Suresh Selvarasu Andrea Camattari Jimyoung Ryu Hyeokweon Lee Jungoh Ahn Hongweon Lee Dong-Yup Lee 《Microbial cell factories》2010,9(1):50
Background
Pichia pastoris has been recognized as an effective host for recombinant protein production. A number of studies have been reported for improving this expression system. However, its physiology and cellular metabolism still remained largely uncharacterized. Thus, it is highly desirable to establish a systems biotechnological framework, in which a comprehensive in silico model of P. pastoris can be employed together with high throughput experimental data analysis, for better understanding of the methylotrophic yeast's metabolism. 相似文献3.
In recent years, genome-sequencing projects of pathogens and humans have revolutionized microbial drug target identification. Of the several known genomic strategies, subtractive genomics has been successfully utilized for identifying microbial drug targets. The present work demonstrates a novel genomics approach in which codon adaptation index (CAI), a measure used to predict the translational efficiency of a gene based on synonymous codon usage, is coupled with subtractive genomics approach for mining potential drug targets. The strategy adopted is demonstrated using respiratory pathogens, namely, Streptococcus pneumoniae and Haemophilus influenzae as examples. Our approach identified 8 potent target genes (Streptococcus pneumoniae?C2, H. influenzae?C6), which are functionally significant and also play key role in host-pathogen interactions. This approach facilitates swift identification of potential drug targets, thereby enabling the search for new inhibitors. These results underscore the utility of CAI for enhanced in silico drug target identification. 相似文献
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5.
This commentary highlights the effectiveness of optoelectronic properties of polymer semiconductors based on recent results emerging from our laboratory, where these materials are explored as artificial receptors for interfacing with the visual systems. Organic semiconductors based polymer layers in contact with physiological media exhibit interesting photophysical features, which mimic certain natural photoreceptors, including those in the retina. The availability of such optoelectronic materials opens up a gateway to utilize these structures as neuronal interfaces for stimulating retinal ganglion cells. In a recently reported work entitled “A polymer optoelectronic interface provides visual cues to a blind retina,” we utilized a specific configuration of a polymer semiconductor device structure to elicit neuronal activity in a blind retina upon photoexcitation. The elicited neuronal signals were found to have several features that followed the optoelectronic response of the polymer film. More importantly, the polymer-induced retinal response resembled the natural response of the retina to photoexcitation. These observations open up a promising material alternative for artificial retina applications. 相似文献
6.
Background
Influenza pandemic remains a serious threat to human health. Viruses of avian origin, H5N1, H7N7 and H9N2, have repeatedly crossed the species barrier to infect humans. Recently, a novel strain originated from swine has evolved to a pandemic. This study aims at improving our understanding on the pathogenic mechanism of influenza viruses, in particular the role of non-structural (NS1) protein in inducing pro-inflammatory and apoptotic responses.Methods
Human lung epithelial cells (NCI-H292) was used as an in-vitro model to study cytokine/chemokine production and apoptosis induced by transfection of NS1 mRNA encoded by seven infleunza subtypes (seasonal and pandemic H1, H2, H3, H5, H7, and H9), respectively.Results
The results showed that CXCL-10/IP10 was most prominently induced (> 1000 folds) and IL-6 was slightly induced (< 10 folds) by all subtypes. A subtype-dependent pattern was observed for CCL-2/MCP-1, CCL3/MIP-1α, CCL-5/RANTES and CXCL-9/MIG; where induction by H5N1 was much higher than all other subtypes examined. All subtypes induced a similar temporal profile of apoptosis following transfection. The level of apoptosis induced by H5N1 was remarkably higher than all others. The cytokine/chemokine and apoptosis inducing ability of the 2009 pandemic H1N1 was similar to previous seasonal strains.Conclusions
In conclusion, the NS1 protein encoded by H5N1 carries a remarkably different property as compared to other avian and human subtypes, and is one of the keys to its high pathogenicity. NCI-H292 cells system proves to be a good in-vitro model to delineate the property of NS1 proteins.7.
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9.
Kulandaivelu S. Vetrivel Xavier Meckler Ying Chen Phuong D. Nguyen Nabil G. Seidah Robert Vassar Philip C. Wong Masaki Fukata Maria Z. Kounnas Gopal Thinakaran 《The Journal of biological chemistry》2009,284(6):3793-3803
Alzheimer disease β-amyloid (Aβ) peptides are generated via
sequential proteolysis of amyloid precursor protein (APP) by BACE1 and
γ-secretase. A subset of BACE1 localizes to cholesterol-rich membrane
microdomains, termed lipid rafts. BACE1 processing in raft microdomains of
cultured cells and neurons was characterized in previous studies by disrupting
the integrity of lipid rafts by cholesterol depletion. These studies found
either inhibition or elevation of Aβ production depending on the extent
of cholesterol depletion, generating controversy. The intricate interplay
between cholesterol levels, APP trafficking, and BACE1 processing is not
clearly understood because cholesterol depletion has pleiotropic effects on
Golgi morphology, vesicular trafficking, and membrane bulk fluidity. In this
study, we used an alternate strategy to explore the function of BACE1 in
membrane microdomains without altering the cellular cholesterol level. We
demonstrate that BACE1 undergoes S-palmitoylation at four Cys
residues at the junction of transmembrane and cytosolic domains, and Ala
substitution at these four residues is sufficient to displace BACE1 from lipid
rafts. Analysis of wild type and mutant BACE1 expressed in BACE1 null
fibroblasts and neuroblastoma cells revealed that S-palmitoylation
neither contributes to protein stability nor subcellular localization of
BACE1. Surprisingly, non-raft localization of palmitoylation-deficient BACE1
did not have discernible influence on BACE1 processing of APP or secretion of
Aβ. These results indicate that post-translational
S-palmitoylation of BACE1 is not required for APP processing, and
that BACE1 can efficiently cleave APP in both raft and non-raft
microdomains.Alzheimer disease-associated β-amyloid
(Aβ)3 peptides
are derived from the sequential proteolysis of β-amyloid precursor
protein (APP) by β- and γ-secretases. The major β-secretase is
an aspartyl protease, termed BACE1 (β-site
APP-cleaving enzyme 1)
(1–4).
BACE1 cleaves APP within the extracellular domain of APP, generating the N
terminus of Aβ. In addition, BACE1 also cleaves to a lesser extent within
the Aβ domain between Tyr10 and Glu11
(β′-cleavage site). Processing of APP at these sites results in the
shedding/secretion of the large ectodomain (sAPPβ) and generating
membrane-tethered C-terminal fragments +1 and +11 (β-CTF)
(5). The multimeric
γ-secretase cleaves at multiple sites within the transmembrane domain of
β-CTF, generating C-terminal heterogeneous Aβ peptides (ranging in
length between 38 and 43 residues) that are secreted, as well as cytosolic APP
intracellular domains (6). In
addition to BACE1, APP can be cleaved by α-secretase within the Aβ
domain between Lys16 and Leu17, releasing sAPPα
and generating α-CTF. γ-Secretase cleavage of α-CTF
generates N-terminal truncated Aβ, termed p3.Genetic ablation of BACE1 completely abolishes Aβ production,
establishing BACE1 as the major neuronal enzyme responsible for initiating
amyloidogenic processing of APP
(4,
7). Interestingly, both the
expression and activity of BACE1 is specifically elevated in neurons adjacent
to senile plaques in brains of individuals with Alzheimer disease
(8). In the past few years
additional substrates of BACE1 have been identified that include APP
homologues APLP1 and APLP2 (9),
P-selectin glycoprotein ligand-1
(10), β-galactoside
α2,6-sialyltransferase
(11), low-density lipoprotein
receptor-related protein (12),
β-subunits of voltage-gated sodium channels
(13), and neuregulin-1
(14,
15), thus extending the
physiological function of BACE1 beyond Alzheimer disease pathogenesis.BACE1 is a type I transmembrane protein with a long extracellular domain
harboring a catalytic domain and a short cytoplasmic tail. BACE1 is
synthesized as a proenzyme, which undergoes post-translational modifications
that include removal of a pro-domain by a furin-like protease,
N-glycosylation, phosphorylation, S-palmitoylation, and
acetylation, during the transit in the secretory pathway
(16–20).
In non-neuronal cells the majority of BACE1 localizes to late Golgi/TGN and
endosomes at steady-state and a fraction of BACE1 also cycles between the cell
surface and endosomes (21).
The steady-state localization of BACE1 is consistent with the acidic pH
optimum of BACE1 in vitro, and BACE1 cleavage of APP is observed in
the Golgi apparatus, TGN, and endosomes
(22–25).
BACE1 endocytosis and recycling are mediated by the GGA family of adaptors
binding to a dileucine motif (496DISLL) in its cytoplasmic tail
(21,
26–31).
Phosphorylation at Ser498 within this motif modulates GGA-dependent
retrograde transport of BACE1 from endosomes to TGN
(21,
26–31).Over the years, a functional relationship between cellular cholesterol
level and Aβ production has been uncovered, raising the intriguing
possibility that cholesterol levels may determine the balance between
amyloidogenic and non-amyloidogenic processing of APP
(32–34).
Furthermore, several lines of evidence from in vitro and in
vivo studies indicate that cholesterol- and sphingolipid-rich membrane
microdomains, termed lipid rafts, might be the critical link between
cholesterol levels and amyloidogenic processing of APP. Lipid rafts function
in the trafficking of proteins in the secretory and endocytic pathways in
epithelial cells and neurons, and participate in a number of important
biological functions (35).
BACE1 undergoes S-palmitoylation
(19), a reversible
post-translational modification responsible for targeting a variety of
peripheral and integral membrane proteins to lipid rafts
(36). Indeed, a significant
fraction of BACE1 is localized in lipid raft microdomains in a
cholesterol-dependent manner, and addition of glycosylphosphatidylinositol
(GPI) anchor to target BACE1 exclusively to lipid rafts increases APP
processing at the β-cleavage site
(37,
38). Antibody-mediated
co-patching of cell surface APP and BACE1 has provided further evidence for
BACE1 processing of APP in raft microdomains
(33,
39). Components of the
γ-secretase complex also associate with detergent-resistant membrane
(DRM) fractions enriched in raft markers such as caveolin, flotillin, PrP, and
ganglioside GM1 (40). The
above findings suggest a model whereby APP is sequentially processed by BACE1
and γ-secretase in lipid rafts.Despite the accumulating evidence, cleavage of APP by BACE1 in non-raft
membrane regions cannot be unambiguously ruled out because of the paucity of
full-length APP (APP FL) and BACE1 in DRM isolated from adult brain and
cultured cells (41). Moreover,
it was recently reported that moderate reduction of cholesterol (<25%)
displaces BACE1 from raft domains, and increases BACE1 processing by promoting
the membrane proximity of BACE1 and APP in non-raft domains
(34). Nevertheless, this study
also found that BACE1 processing of APP is inhibited with further loss of
cholesterol (>35%), consistent with earlier studies
(32,
33). Nevertheless, given the
pleiotropic effects of cholesterol depletion on membrane properties and
vesicular trafficking of secretory and endocytic proteins
(42–47),
unequivocal conclusions regarding BACE1 processing of APP in lipid rafts
cannot be reached based on cholesterol depletion studies.In this study, we explored the function of BACE1 in lipid raft microdomains
without manipulating cellular cholesterol levels. In addition to the
previously reported S-palmitoylation sites
(Cys478/Cys482/Cys485) within the cytosolic
tail of BACE1 (19), we have
identified a fourth site (Cys474) within the transmembrane domain
of BACE1 that undergoes S-palmitoylation. A BACE1 mutant with Ala
substitution of all four Cys residues (BACE1-4C/A) fails to associate with DRM
in cultured cells, but is not otherwise different from wtBACE1 in terms of
protein stability, maturation, or subcellular localization. Surprisingly, APP
processing and Aβ generation were unaffected in cells stably expressing
the BACE1-4C/A mutant. Finally, we observed an increase in the levels of APP
CTFs in detergent-soluble fractions of BACE1-4C/A as compared with wtBACE1
cells. Thus, our data collectively indicate a non-obligatory role of
S-palmitoylation and lipid raft localization of BACE1 in
amyloidogenic processing of APP. 相似文献
10.
Modeling of phosphomethyl pyrimidine kinase from Leptospira interrogans serovar lai strain 56601
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Many microorganisms, as well as plants and fungi, synthesize thiamin, but vertebrates do not produce it. Phosphomethyl pyrimidine kinase is an enzyme involved in an intermediary step of thiamin biosynthesis from purine molecules. This enzyme is absent in humans. Thus, it is a potential chemotherapeutic target for antileptospiral treatment. Structure of this enzyme from Leptospira interrogans serovar lai strain 56601 has not yet been elucidated. We used the structural template of phosphomethyl pyrimidine kinase from Thermus thermophilus HB8 for modeling the phosphomethyl pyrimidine kinase structure from Leptospira interrogans serovar lai strain 56601 . The model is deposited in Protein Data Bank (PDB ID: 2G53) at RCSB. Thus, we analyse and propose the usefulness of the modeled phosphomethyl pyrimidine kinase for the design of suitable inhibitors towards the treatment of leptospirosis. 相似文献