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At least 235 records · Page 13Linked to original sources

PubMed1997

Construction of hydrodynamic bead models from high-resolution X-ray crystallographic or nuclear magnetic resonance data.

Computer software such as HYDRO, based upon a comprehensive body of theoretical work, permits the hydrodynamic modeling of macromolecules in solution, which are represented to the computer interface as an assembly of spheres. The uniqueness of any satisfactory resultant model is optimized by incorporating into the modeling procedure the maximal possible number of criteria to which the bead model must conform. An algorithm (AtoB, for atoms to beads) that permits the direct construction of bead models from high resolution x-ray crystallographic or nuclear magnetic resonance data has now been formulated and tested. Models so generated then act as informed starting estimates for the subsequent iterative modeling procedure, thereby hastening the convergence to reasonable representations of solution conformation. Successful application of this algorithm to several proteins shows that predictions of hydrodynamic parameters, including those concerning solvation, can be confirmed.

Algorithms↗

PubMed1999

Cellular recognition of synthetic peptide amphiphiles in self-assembled monolayer films.

The incorporation of lipidated cell adhesion peptides into self-assembled structures such as films provides the opportunity to develop unique biomimetic materials with well-organized interfaces. Synthetic dialkyl tails have been linked to the amino-terminus, carboxyl-terminus, and both termini of the cell recognition sequence Arg-Gly-Asp (RGD) to produce amino-coupled, carboxyl-coupled, and looped RGD peptide amphiphiles. All three amphiphilic RGD versions self-assembled into fairly stable mixed monolayers that deposited well as Langmuir-Blodgett films on surfaces, except for films containing amino-coupled RGD amphiphiles at high peptide concentrations. FT-IR studies showed that amino-coupled RGD head groups formed the strongest lateral hydrogen bonds. Melanoma cells spread on looped RGD amphiphiles in a concentration-dependent manner, spread indiscriminately on carboxyl-coupled RGD amphiphiles, and did not spread on amino-coupled RGD amphiphiles. Looped RGD amphiphiles promoted the adhesion, spreading, and cytoskeletal reorganization of melanoma and endothelial cells while control looped Arg-Gly-Glu (RGE) amphiphiles inhibited them. Antibody inhibition of the integrin receptor alpha3beta1 blocked melanoma cell adhesion to looped RGD amphiphiles. These results confirm that novel biomolecular materials containing synthetic peptide amphiphiles have the potential to control cellular behavior in a specific manner.

Actins↗

PubMed2002

Monomeric structures of the zymogen and active catalytic domain of complement protease c1r: further insights into the c1 activation mechanism.

C1r is the serine protease (SP) that mediates autoactivation of C1, the complex that triggers the classical complement pathway. We have determined the crystal structure of two fragments from the human C1r catalytic domain, each encompassing the second complement control protein (CCP2) module and the SP domain. The wild-type species has an active structure, whereas the S637A mutant is a zymogen. The structures reveal a restricted hinge flexibility of the CCP2-SP interface, and both are characterized by the unique alpha-helical conformation of loop E. The zymogen activation domain exhibits high mobility, and the active structure shows a restricted access to most substrate binding subsites. Further implications relevant to the C1r self-activation process are derived from protein-protein interactions in the crystals.

Binding Sites↗

PubMed2001

Structural basis of Smad1 activation by receptor kinase phosphorylation.

Phosphorylation of Smad1 at the conserved carboxyl terminal SVS sequence activates BMP signaling. Here we report the crystal structure of the Smad1 MH2 domain in a conformation that reveals the structural effects of phosphorylation and a molecular mechanism for activation. Within a trimeric subunit assembly, the SVS sequence docks near two putative phosphoserine binding pockets of the neighboring molecule, in a position ready to interact upon phosphorylation. The MH2 domain undergoes concerted conformational changes upon activation, which signal Smad1 dissociation from the receptor kinase for subsequent heteromeric assembly with Smad4. Biochemical and modeling studies reveal unique favorable interactions within the Smad1/Smad4 heteromeric interface, providing a structural basis for their association in signaling.

Allosteric Regulation↗

PubMed2003

Lipase assays for conventional and molecular screening: an overview.

Lipases are versatile biocatalysts that can perform innumerable different reactions. Their enantio-, chemo- and stereo-selective nature makes them an important tool in the area of organic synthesis. Unlike other hydrolases that work in aqueous phase, lipases are unique as they act at the oil/water interface. Besides being lipolytic, lipases also possess esterolytic activity and thus have a wide substrate range. Hence, the lipase assay protocols hold a significant position in the field of lipase research. Lipase activity can be estimated using a wide range of assay protocols that differ in terms of their basic principle, substrate selectivity, sensitivity and applicability. As the value of these enzymes continues to grow and new markets are exploited, development of new or improved enzymes will be a key element in the emerging realm of biotechnology. Hence, development of faster and simpler protocols incorporating newer and more specific substrates is the need of the hour. In this endeavour, methods that could be adopted for molecular screening occupy an important position. Here, an overview of the lipase assay protocols is presented with emphasis on the assays that can be adopted for the molecular screening of these biocatalysts.

Enzyme Activation↗

PubMed2005

BAR domains and membrane curvature: bringing your curves to the BAR.

BAR (bin, amphiphysin and Rvs161/167) domains are a unique class of dimerization domains, whose dimerization interface is edged by a membrane-binding surface. In its dimeric form, the membrane-binding interface is concave, and this gives the ability to bind better to curved membranes, i.e. to sense membrane curvature. When present at higher concentrations, the domain can stabilize membrane curvature, generating lipid tubules. This domain is found in many contexts in a wide variety of proteins, where the dimerization and membrane-binding function of this domain is likely to have a profound effect on protein activity. If these proteins function as predicted, then there will be membrane subdomains based on curvature, and thus there is an additional layer of compartmentalization on membranes. These and other possible functions of the BAR domain are discussed.

Amino Acid Sequence↗

PubMed2000

Allergen sensitization through the skin induces systemic allergic responses.

The skin is a unique immunologic organ that acts as an interface between the external environment and the systemic immune response. As such, it may react directly with allergens that are applied epicutaneously, thereby influencing the systemic allergic response. It is well known that atopic dermatitis (frequently in association with food allergy) predates the development of asthma and allergic rhinitis by several years. The possibility that atopic dermatitis may influence the course of asthma is suggested by several interesting observations. First, children with atopic dermatitis and positive skin tests to allergens frequently have more severe asthma than asthmatic children without atopic dermatitis. Second, because total serum IgE is strongly associated with the prevalence of asthma, it raises the interesting question of whether allergen sensitization through the skin predisposes to more severe and persistent respiratory disease because of its effects on the systemic allergic response. Indeed, epicutaneous sensitization of mice to a protein antigen induces both a localized allergic dermatitis and hyperresponsiveness to methacholine, which suggests that epicutaneous exposure to antigen in atopic dermatitis may enhance the development of asthma. Finally, systemic immune activation in atopic dermatitis is supported by the observation that these patients have increased numbers of circulating activated T(H)2 cells, eosinophils, macrophages, and IgE. Many of the markers of leukocyte activation have been shown to correlate with the severity of atopic dermatitis disease. This systemic activation might facilitate local infiltration of primed T cells, eosinophils, and macrophages into the respiratory mucosa after inhalation of allergen in genetically predisposed hosts. The systemic aspects of atopic dermatitis, with an emphasis on respiratory effects, are summarized.

Allergens↗

PubMed2002

Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1.

Nurr1, an orphan nuclear receptor mainly expressed in the central nervous system, is essential for the development of the midbrain dopaminergic neurons. Nurr1 binds DNA as a monomer and exhibits constitutive transcriptional activity. Nurr1 can also regulate transcription as a heterodimer with the retinoid X receptor (RXR) and activate transcription in response to RXR ligands. However, the specific physiological roles of Nurr1 monomers and RXR-Nurr1 heterodimers remain to be elucidated. The aim of this study was to define structural requirements for RXR-Nurr1 heterodimerization. Several amino acid substitutions were introduced in both Nurr1 and RXR in the I-box, a region previously shown to be important for nuclear receptor dimerization. Single amino acid substitutions introduced in either Nurr1 or RXR abolished heterodimerization. Importantly, heterodimerization-deficient Nurr1 mutants exhibited normal activities as monomers. Thus, by introducing specific amino acid substitutions in Nurr1, monomeric and heterodimeric properties of Nurr1 can be distinguished. Interestingly, substitutions in the RXR I-box differentially affected heterodimerization with Nurr1, retinoic acid receptor, thyroid hormone receptor, and constitutive androstane receptor demonstrating that the dimerization interfaces in these different heterodimers are functionally unique. Furthermore, heterodimerization between RXR and Nurr1 had a profound influence on the constitutive activity of Nurr1, which was diminished as a result of RXR interaction. In conclusion, our data show unique structural and functional properties of RXR-Nurr1 heterodimers and also demonstrate that specific mutations in Nurr1 can abolish heterodimerization without affecting other essential functions.

Amino Acid Sequence↗

PubMed2004

Nucleotide binding induces conformational changes in Escherichia coli transcription termination factor Rho.

The Escherichia coli Rho protein uses the energy of ATP binding and hydrolysis to translocate along RNA and cause transcription termination. Using fluorescence stopped-flow kinetic studies, we have discerned the conformational changes in the Rho protein that occur upon nucleotide and nucleic acid binding. We show that the 2', (3')-O-[N-methylanthraniloyl] derivative of ATP (mant-ATP) is a good fluorescent substrate of Rho and is hydrolyzed with a K(m) comparable with that for ATP but a k(cat) five to six times slower than that for ATP. The kinetics of ATP and mant-ATP binding indicates that, in the absence of RNA, the Rho protein is structurally distinct from the Rho hexamer found when bound to RNA or DNA. In the absence of RNA, the nucleotide-binding rates are 50- to 70-fold slower, and the dissociation rates are 40- to 120-fold slower than the corresponding rates in the presence of RNA. We conclude that RNA or DNA binding to the primary nucleic acid binding sites causes conformational changes in the Rho hexamer that result in the opening of the subunit interfaces. Furthermore, the kinetic studies revealed a unique protein conformational change in the Rho.RNA complex upon ATP binding that is a result of RNA contacting the secondary nucleic acid binding sites in the central channel of the Rho ring. This conformational change seems to render the Rho ring competent in ATP hydrolysis and translocation.

Adenosine Triphosphate↗

PubMed2006

Crystal structure of the human BRD2 bromodomain: insights into dimerization and recognition of acetylated histone H4.

The BET (bromodomains and extra terminal domain) family proteins recognize acetylated chromatin through their bromodomain and act as transcriptional activators. One of the BET proteins, BRD2, associates with the transcription factor E2F, the mediator components CDK8 and TRAP220, and RNA polymerase II, as well as with acetylated chromatin during mitosis. BRD2 contains two bromodomains (BD1 and BD2), which are considered to be responsible for binding to acetylated chromatin. The BRD2 protein specifically recognizes the histone H4 tail acetylated at Lys12. Here, we report the crystal structure of the N-terminal bromodomain (BD1, residues 74-194) of human BRD2. Strikingly, the BRD2 BD1 protein forms an intact dimer in the crystal. This is the first observation of a homodimer among the known bromodomain structures, through the buried hydrophobic core region at the interface. Biochemical studies also demonstrated BRD2 BD1 dimer formation in solution. The two acetyllysine-binding pockets and a negatively charged secondary binding pocket, produced at the dimer interface in BRD2 BD1, may be the unique features that allow BRD2 BD1 to selectively bind to the acetylated H4 tail.

Acetylation↗

PubMed2003

European Emergency Data Project (EED Project): EMS data-based health surveillance system.

Emergency Medical Services (EMS) constitute a unique component of health care at the interface between primary and hospital care. EMS data within the pre-hospital setting represents an unparalleled source of epidemiological and health care information that have so far been neglected for public health monitoring. The European Emergency Data Project (EED Project) thus intends to identify common indicators for European EMS systems and to evaluate their suitability for integration into a comprehensive public health monitoring strategy. The article provides a brief overview on objectives and methodology in the form of a progress report.

Benchmarking↗

PubMed2005

enoLOGOS: a versatile web tool for energy normalized sequence logos.

enoLOGOS is a web-based tool that generates sequence logos from various input sources. Sequence logos have become a popular way to graphically represent DNA and amino acid sequence patterns from a set of aligned sequences. Each position of the alignment is represented by a column of stacked symbols with its total height reflecting the information content in this position. Currently, the available web servers are able to create logo images from a set of aligned sequences, but none of them generates weighted sequence logos directly from energy measurements or other sources. With the advent of high-throughput technologies for estimating the contact energy of different DNA sequences, tools that can create logos directly from binding affinity data are useful to researchers. enoLOGOS generates sequence logos from a variety of input data, including energy measurements, probability matrices, alignment matrices, count matrices and aligned sequences. Furthermore, enoLOGOS can represent the mutual information of different positions of the consensus sequence, a unique feature of this tool. Another web interface for our software, C2H2-enoLOGOS, generates logos for the DNA-binding preferences of the C2H2 zinc-finger transcription factor family members. enoLOGOS and C2H2-enoLOGOS are accessible over the web at http://biodev.hgen.pitt.edu/enologos/.

Amino Acids↗

PubMed2004

Evaporation-driven assembly of colloidal particles.

Colloidal particles absorbed at the interface of a liquid droplet arrange into unique packings during slow evaporation [V.N. Manoharan et al., Science 301, 483 (2003)]. We present a numerical and theoretical analysis of the packing selection problem. The selection of a unique packing arises almost entirely from geometrical constraints during the drying.

Biophysics↗

PubMed2004

Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting.

Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as TR3 [corrected] or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXRalpha is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXRalpha are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXRalpha ligands suppress NES activity by inducing RXRalpha homodimerization or altering RXRalpha/Nur77 heterodimerization. The RXRalpha NES is also silenced by RXRalpha heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXRalpha/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXRalpha and its involvement in the regulation of the Nur77-dependent apoptotic pathway [corrected]

Active Transport, Cell Nucleus↗

PubMed1992

Results of implant retrieval from postmortem specimens in patients with well-functioning, long-term total hip replacement.

The evaluation of postmortem specimens provides a unique opportunity to gain understanding of the interface between host and well-functioning prostheses unavailable from revision specimens that, by nature, are accompanied by the artifacts generated during their removal. The preliminary findings from the relatively limited number of specimens described in this collaborative study demonstrate the value of the effort and are presented to encourage surgeons to participate in this program and to make their patients aware of the value of the information they may provide.

Adult↗

PubMed1994

Extensive lipidation of a Torpedo cysteine string protein.

Cysteine string proteins are relatively low mass components of synaptic vesicle membranes. Structurally, their primary sequence is distinguished by a remarkable, cysteine-rich motif. Investigations revealed an unprecedented degree of lipidation of these cysteine residues. At least 11 of the 13 cysteines of the Torpedo protein were modified, principally by palmitoyl moieties. This fatty acylation creates a prominent hydrophobic domain flanked by polar amino and carboxyl termini. An amphipathic structure of this type is uniquely suited to mediate events at membrane interfaces. Thus, cysteine string proteins are candidates to participate in exocytotic membrane fusion.

Animals↗

PubMed2004

A review of pollutants in the sea-surface microlayer (SML): a unique habitat for marine organisms.

Boundary layers between different environmental compartments represent critical interfaces for biological, chemical and physical processes. The sea-surface microlayer (uppermost 1-1000 microm layer) forms the boundary layer interface between the atmosphere and ocean. Environmental processes are controlled by the SML, and it is known to play a key role in the global distribution of anthropogenic pollutants. Due to its unique chemical composition, the upper organic film of the SML represents both a sink and a source for a range of pollutants including chlorinated hydrocarbons, organotin compounds, petroleum hydrocarbons, polycyclic aromatic hydrocarbons (PAH) and heavy metals. These pollutants can be enriched in the SML by up to 500 times relative to concentrations occurring in the underlying bulk water column. The SML is also a unique ecosystem, serving as an important habitat for fish eggs and larvae. Concentration ranges and enrichment factors of pollutants in the SML in different areas of the world's oceans have been critically reviewed, together with available toxicity data for marine biota found within the SML. Overall, the SML is highly contaminated in many urban and industrialized areas of the world, resulting in severe ecotoxicological impacts. Such impacts may lead to drastic effects on the marine food web and to fishery recruitment in coastal waters. Studies of the toxicity of fish eggs and larvae exposed to the SML contaminants have shown that the SML in polluted areas leads to significantly higher rates of mortality and abnormality of fish embryos and larvae.

Animals↗

PubMed2004

The nuclease domain of adeno-associated virus rep coordinates replication initiation using two distinct DNA recognition interfaces.

Integration into a particular location in human chromosomes is a unique property of the adeno-associated virus (AAV). This reaction requires the viral Rep protein and AAV origin sequences. To understand how Rep recognizes DNA, we have determined the structures of the Rep endonuclease domain separately complexed with two DNA substrates: the Rep binding site within the viral inverted terminal repeat and one of the terminal hairpin arms. At the Rep binding site, five Rep monomers bind five tetranucleotide direct repeats; each repeat is recognized by two Rep monomers from opposing faces of the DNA. Stem-loop binding involves a protein interface on the opposite side of the molecule from the active site where ssDNA is cleaved. Rep therefore has three distinct binding sites within its endonuclease domain for its different DNA substrates. Use of these different interfaces generates the structural asymmetry necessary to regulate later events in viral replication and integration.

Binding Sites↗