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At least 883 records · Page 49Linked to original sources
PubMed2026

A noncontiguous code for RNA-guided DNA recognition at the origin of CRISPR-Cas.

CRISPR-Cas provides RNA-mediated adaptive immunity, but how its first RNA-guided effector arose is unclear. In this study, we report the discovery of Viral Interference Programmable Repeat (VIPR) systems consisting of a Vipr protein ancestral to the earliest CRISPR-Cas effectors and VIPR RNAs (vrRNAs) comprising alternating GGY/NN motifs. Unlike canonical guide RNAs that pair with target nucleic acids through contiguous complementarity, vrRNAs recognize double-stranded DNA through a noncontiguous code in which the variable NN dinucleotides collectively specify a gapped target sequence. Natural vrRNA targets suggest that VIPR systems act against competing phages, and we demonstrate programmable phage defense by redirecting the complex for transcriptional repression. These results suggest that adaptive immunity originated from ancient warfare between viruses, revealing a previously unidentified logic for encoding information in sequence.

CRISPR-Cas Systems↗
PubMed2004

Apoptosis as a mechanism for cell surface expression of the autoantigen pyruvate dehydrogenase complex.

A number of antigens implicated in the pathogenesis of autoimmune diseases including Sjogren's syndrome and systemic lupus erythematosus (SLE) are expressed aberrantly by apoptotic cells. It is also known that apoptogenic proteins are released from the mitochondrial intermembrane space at an early stage during the induction and development of apoptosis. Combination of this evidence led us to test the hypothesis that apoptotic mechanisms provide an explanation for the abnormal expression of the inner mitochondrial enzyme, pyruvate dehydrogenase complex (PDC), observed on the surface of some cells in patients with the autoimmune liver disease primary biliary cirrhosis (PBC). Using one murine and two human cell lines it was found that the induction of apoptosis led to early detection of PDC within the cytoplasm. However, cytochrome c oxidase subunit 4 (COX 4), which is also present on the inner surface of the inner mitochondrial membrane, remained within the mitochondria. Immunoreactive PDC was also detected on the outer surface of the intact plasma membrane of cells sampled after the induction of apoptosis. Serial release of PDC to the cytoplasm and then onto the external surface of the plasma membrane provides direct evidence that the antigen on the cell surface is of mitochondrial origin. Immunoreactivity specific for PDC is strongly implicated in the pathogenesis of PBC, but this autoantigen is normally concealed from the immune system by three membrane systems. Release of PDC onto the cell surface during apoptosis provides a possible route for recognition of this antigen by the immune system which could contribute to both afferent and efferent phases of the disease process.

Animals↗
PubMed1991

Some thoughts on impossible figures.

Based on an artistic analysis of the construction of "impossible figures," their structure and the origin of the perceptual effects they induce are discussed, including the use of a basic indeterminate space of intersection, penetration of indeterminate solids, and symmetry. These and other points are illustrated by 17 progressively more complex figures constructed by the author.

Attention↗
PubMed2002

Genetically engineered gold-binding polypeptides: structure prediction and molecular dynamics.

The biological control of inorganic crystal formation, morphology, and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to materials scientists using biomimetic approaches for the control of inorganic material fabrication and assembly. Biomimetics requires an accurate understanding of natural mechanisms at the molecular level. Such understanding can be derived from the use of metal surfaces to study surface recognition by proteins together with combinatorial genetics techniques for the selection of suitable peptides. Polymerization of these peptides produces engineered polypeptides large enough to encode their own folding information with low structural complexity, while enhancing binding affinity to surfaces. The low complexity of such polypeptides can aid in analyses, leading to modeling and eventual manipulation of the structure of the folded polypeptide. This paper presents structure predictions for gold-binding protein sequences, originally selected by combinatorial techniques. Molecular dynamics simulations lasting 5 ns were carried out using solvated polypeptides at the gold surface to assess the dynamics of the binding process and the effects of surface topography on the specificity of protein binding.

Amino Acid Sequence↗
PubMed2000

Regulation of the adhesion versus cytotoxic functions of the Mac-1/CR3/alphaMbeta2-integrin glycoprotein.

Mac-1/CR3 functions as both an adhesion molecule mediating the diapedesis of leukocytes across the endothelium and a receptor for the iC3b fragment of complement responsible for phagocytic/degranulation responses to microorganisms. Mac-1/CR3 has many functional characteristics shared with other integrins, including bidirectional signaling via conformational changes that originate in either the cytoplasmic domain or extracellular region. Another key to its functions is its ability to form membrane complexes with glycosylphosphatidylinositol (GPI)-anchored receptors such as Fc gammaRIIIB (CD16b) or uPAR (CD87), providing a transmembrane signaling mechanism for these outer membrane bound receptors that allows them to mediate cytoskeleton-dependent adhesion or phagocytosis and degranulation. Many functions appear to depend upon a membrane-proximal lectin site responsible for recognition of either microbial surface polysaccharides or GPI-linked signaling partners. Because of the importance of Mac-1/CR3 in promoting neutrophil inflammatory responses, therapeutic strategies to antagonize its functions have shown promise in treating both autoimmune diseases and ischemia/reperfusion injury. Conversely, soluble beta-glucan polysaccharides that bind to its lectin site prime the Mac-1/CR3 of circulating phagocytes and natural killer (NK) cells, permitting cytotoxic degranulation in response to iC3b-opsonized tumor cells that otherwise escape from this mechanism of cell-mediated cytotoxicity.

Antibodies, Monoclonal↗
PubMed2000

Diatom fucoxanthin chlorophyll a/c-binding protein (FCP) and land plant light-harvesting proteins use a similar pathway for thylakoid membrane Insertion.

The light-harvesting proteins in plastids of different lineages including algae and land plants represent a superfamily of chlorophyll-binding proteins that seem to be phylogenetically related, although some of the light-harvesting complex (LHC) proteins bind different carotenoids. LHCs can be divided into chlorophyll a/b-binding proteins found in green algae, euglenoids, and higher plants and into chlorophyll a/c-binding proteins of various algal taxa. LHC proteins from diatoms are named fucoxanthin-chlorophyll a/c-binding proteins (FCP). In contrast to chlorophyll a/b-binding proteins, there is no information so far about the way FCPs integrate into thylakoid membranes. The diatom FCP preproteins have a bipartite presequence that is necessary to enable transport into the four membrane-bound diatom plastids, but similar to chlorophyll a/b-binding proteins there is apparently no presequence present for targeting to the thylakoid membrane. By establishing an in vitro import assay for diatom thylakoids, we demonstrated that thylakoid integration of diatom FCP depends on the presence of stromal factors and GTP. This indicates that a pathway involving signal recognition particles (SRP) is involved in membrane integration just as shown for LHCs in higher plants. We also demonstrate integration of diatom FCP into thylakoids of higher plants and vice versa SRP-dependent targeting of LHCs from pea and Arabidopsis into diatom thylakoids. The similar SRP-dependent modes of thylakoid integration of land plant LHCs and FCPs support recent analyses indicating a common origin of chlorophyll a/b- and a/c-binding proteins.

Amino Acid Sequence↗
PubMed2006

Shape-specific recognition in the structure of the Vts1p SAM domain with RNA.

Although the abundant sterile alpha motif (SAM) domain was originally classified as a protein-protein interaction domain, it has recently been shown that certain SAM domains have the ability to bind RNA, defining a new type of post-transcriptional gene regulator. To further understand the function of SAM-RNA recognition, we determined the solution structures of the SAM domain of the Saccharomyces cerevisiae Vts1p (Vts1p-SAM) and the Smaug response element (SRE) stem-loop RNA as a complex and in isolation. The structures show that Vts1p-SAM recognizes predominantly the shape of the SRE rather than its sequence, with the exception of a G located at the tip of the pentaloop. Using microarray gene profiling, we identified several genes in S. cerevisiae that seem to be regulated by Vts1p and contain one or more copies of the SRE.

Amino Acid Sequence↗
PubMed1981

[Aspects of depression (author's transl)].

Ernst underlines the complexities of the various depressive conditions and briefly indicates what may be the development and limits of depression. The text ranges from the monosymptomatic forms (where lack of affect, insomnia or hypochondria are themselves presenting symptoms), to the depression of menopause and depression of retirement which are associated with psychic origins. It is emphasised that although the difference between a depressive state and a neurosis is a relative one, certain signs permit the recognition of the depression. These include: - chronicity; attacks of melancholy in contrast to chronic depression; - bodily perceptions, where the symptomatology of depression is identified directly with an organ or system; - the idea of death which represents the common denominator of these conditions.

Adjustment Disorders↗
PubMed2001

Electrostatics of cell membrane recognition: structure and activity of neutral and cationic rigid push-pull rods in isoelectric, anionic, and polarized lipid bilayer membranes.

Design, synthesis, and structural and functional studies of rigid-rod ionophores of different axial electrostatic asymmetry are reported. The employed design strategy emphasized presence of (a) a rigid scaffold to minimize the conformational complexity, (b) a unimolecular ion-conducting pathway to minimize the suprastructural complexity and monitor the function, (c) an extended fluorophore to monitor structure, (d) variable axial rod dipole, and (e) variable terminal charges to create axial asymmetry. Studies in isoelectric, anionic, and polarized bilayer membranes confirmed a general increase in activity of uncharged rigid push-pull rods in polarized bilayers. The similarly increased activity of cationic rigid push-pull rods with an electrostatic asymmetry comparable to that of alpha-helical bee toxin melittin (positive charge near negative axial dipole terminus) is shown by fluorescence-depth quenching experiments to originate from the stabilization of transmembrane rod orientation by the membrane potential. The reduced activity of rigid push-pull rods having an electrostatic asymmetry comparable to that in alpha-helical natural antibiotics (a positive charge near the positive axial dipole terminus) is shown by structural studies to originate from rod "ejection" by membrane potentials comparable to that found in mammalian plasma membranes. This structural evidence for cell membrane recognition by asymmetric rods is unprecedented and of possible practical importance with regard to antibiotic resistance.

Amino Acid Sequence↗
PubMed1999

Some anticardiolipin antibodies recognize a combination of phospholipids with thrombin-modified antithrombin, complement C4b-binding protein, and lipopolysaccharide binding protein.

The standard enzyme-linked immunosorbent assay (ELISA) for anticardiolipin antibodies (ACA) detects a heterogenous group of antibodies against cardiolipin on its own, beta2-glycoprotein I (beta2GPI), and, potentially, other phospholipid-binding plasma proteins from bovine or human origin. In an attempt to identify new proteic targets of ACA, we selected 6 patients who possessed cofactor-dependent ACA but no antibody to human or bovine beta2GPI detectable in the beta2GPI-ELISA. Three of these samples proved to recognize beta2GPI in combination with cardiolipin, but not beta2GPI directly immobilized on gamma-irradiated polystyrene or agarose beads. In the other cases, the component required for ACA binding was purified from adult bovine serum or plasma by means of ammonium sulfate precipitation and chromatography on Phenyl-Sepharose, diethyl aminoethyl (DEAE)-cellulose, heparin-Ultrogel, and Sephacryl S-300 columns. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis coupled to N-terminal amino acid microsequencing identified the cofactors of patients no. 4, 5, and 6 ACA as lipopolysaccharide binding protein (LBP), complement C4b-binding protein (C4BP), and the thrombin-antithrombin (AT) complex, respectively. Adsorption of each of these cofactor preparations with cardiolipin liposomes led to suppression of ACA reactivity, concomitant with the loss of bands from SDS gels corresponding to sequenced material. Bacterial lipopolysaccharide (which forms high-affinity complexes with LBP) specifically neutralized the cofactor activity of the LBP preparation in a concentration-dependent manner. Bovine serum and plasma, as well as the C4BP preparation, optimally supported the binding of a rabbit anti-C4BP antiserum to immobilized cardiolipin. The binding of a rabbit anti-AT antiserum to solid-phase cardiolipin was sustained by the thrombin-AT preparation and bovine serum, but neither by bovine plasma nor by native AT, thus reproducing the behavior of patient no. 6 ACA. Taking advantage of the restricted recognition by the latter ACA of a cofactor from bovine origin appearing upon clotting, we studied the generation of such activity in human plasma supplemented with bovine AT or bovine prothrombin before clotting. In these conditions, patient no. 6 antibody binding to cardiolipin required the addition of bovine AT, whereas addition of bovine prothrombin alone was ineffective. We therefore concluded that those ACA targeted bovine AT once it has been modified/cleaved by thrombin. These findings underline the wide heterogeneity of ACA and the links that may exist between various coagulation pathways, inflammation and the complement system.

Acute-Phase Proteins↗
PubMed1994

Phage phi 29 protein p6: a viral histone-like protein.

Phage phi 29 protein p6 is one of the most abundant viral proteins in phi 29-infected B subtilis cells, constituting about 4% of the total cellular proteins (about 3 x 10(6) copies/cell) at late infection. Electron microscopic studies showed that, in vitro, protein p6 forms heterogeneously-sized complexes all along phi 29 DNA, suggesting that protein p6 may have a role in genome packaging and organization. The low stability of the protein p6-phi 29 DNA complexes observed in vitro could reflect the dynamic nature of these complexes, to allow replication, transcription, and encapsidation of the genome. The protein p6-DNA complex consists of a DNA right-handed superhelix wrapped around a multimeric protein core. The DNA in this complex is strongly distorted and compacted. Protein p6 recognition signals have been mapped near the ends of the linear phi 29 DNA and act as nucleation sites for complex formation. Protein p6 does not recognize a specific sequence, but sequences with specific bendable properties that would favor the formation of the complex. Protein p6 represses transcription from the phi 29 C2 early promoter, and activates initiation of phi 29 DNA replication that occurs from both DNA ends. The formation of nucleoprotein complexes at the origins of replication, as well as the specific positioning of protein p6 with respect to the DNA ends are required for the activation of replication. This suggests that the proteins involved in the initiation step of phi 29 DNA replication, either directly interact with protein p6, or recognize a conformational change at a specific location in the DNA. The mechanism of activation could be the local and transient unpairing of DNA at specific sites, facilitated by the strong distortion of DNA conformation in the nucleoprotein complex.

Bacillus Phages↗
PubMed1997

Multiple pathways to bypass the enhancer requirement of sigma 54 RNA polymerase: roles for DNA and protein determinants.

Sigma 54 is a required factor for bacterial RNA polymerase to respond to enhancers and directs a mechanism that is a hybrid between bacterial and eukaryotic transcription. Three pathways were found that bypass the enhancer requirement in vitro. These rely on either deletion of the sigma 54 N terminus or destruction of the DNA consensus -12 promoter recognition element or altering solution conditions to favor transient DNA melting. Each of these allows unstable heparin-sensitive pre-initiation complexes to form that can be driven to transcribe in the absence of both enhancer protein and ATP beta-gamma hydrolysis. These disparate pathways are proposed to have a common basis in that multiple N-terminal contacts may mediate the interactions between the polymerase and the DNA region where melting originates. The results raise possibilities for common features of open complex formation by different RNA polymerases.

Amino Acid Sequence↗
PubMed2000

Radical pruning: a method to construct skeleton radial basis function networks.

Trained radial basis function networks are well-suited for use in extracting rules and explanations because they contain a set of locally tuned units. However, for rule extraction to be useful, these networks must first be pruned to eliminate unnecessary weights. The pruning algorithm cannot search the network exhaustively because of the computational effort involved. It is shown that using multiple pruning methods with smart ordering of the pruning candidates, the number of weights in a radial basis function network can be reduced to a small fraction of the original number. The complexity of the pruning algorithm is quadratic (instead of exponential) in the number of network weights. Pruning performance is shown using a variety of benchmark problems from the University of California, Irvine machine learning database.

Algorithms↗
PubMed2001

Water-assisted dual mode cofactor recognition by HhaI DNA methyltransferase.

Energetically competent binary recognition of the cofactor S-adenosyl-L-methionine (AdoMet) and the product S-adenosyl-L-homocysteine (AdoHcy) by the DNA (cytosine C-5) methyltransferase (M.HhaI) is demonstrated herein. Titration calorimetry reveals a dual mode, involving a primary dominant exothermic reaction followed by a weaker endothermic one, for the recognition of AdoMet and AdoHcy by M.HhaI. Conservation of the bimodal recognition in W41I and W41Y mutants of M.HhaI excludes the cation-pi interaction between the methylsulfonium group of AdoMet and the pi face of the Trp(41) indole ring from a role in its origin. Small magnitude of temperature-independent heat capacity changes upon AdoMet or AdoHcy binding by M.HhaI preclude appreciable conformational alterations in the reacting species. Coupled osmotic-calorimetric analyses of AdoMet and AdoHcy binding by M.HhaI indicate that a net uptake of nearly eight and 10 water molecules, respectively, assists their primary recognition. A change in water activity at constant temperature and pH is sufficient to engender and conserve enthalpy-entropy compensation, consistent with a true osmotic effect. The results implicate solvent reorganization in providing the major contribution to the origin of this isoequilibrium phenomenon in AdoMet and AdoHcy recognition by M.HhaI. The observations provide unequivocal evidence for the binding of AdoMet as well as AdoHcy to M.HhaI in solution state. Isotope partitioning analysis and preincubation studies favor a random mechanism for M.HhaI-catalyzed reaction. Taken together, the results clearly resolve the issue of cofactor recognition by free M.HhaI, specifically in the absence of DNA, leading to the formation of an energetically and catalytically competent binary complex.

Base Sequence↗
PubMed1993

Naming faces and naming names: exploring an interactive activation model of person recognition.

In this paper we present an interactive activation and competition (IAC) model of name recognition. This is an extension of a previous account of name retrieval (Burton & Bruce, 1992) and is based on a functional model due to Valentine, Bredart, Lawson, and Ward (1991). Several empirical effects of name recognition are simulated: (1) names that are known are read faster than names that are unknown; (2) common names are read faster than rare names; and (3) rare names are recognised as familiar faster than common names. The simulations demonstrate that these complex effects can arise as a natural consequence of the architecture of the IAC model. Finally, we explore a modification of the Valentine et al. functional model, and conclude that the model as originally proposed is best able to account for the available data.

Association↗
PubMed2000

Phosphorylated peptides are naturally processed and presented by major histocompatibility complex class I molecules in vivo.

Posttranslational modification of peptide antigens has been shown to alter the ability of T cells to recognize major histocompatibility complex (MHC) class I-restricted peptides. However, the existence and origin of naturally processed phosphorylated peptides presented by MHC class I molecules have not been explored. By using mass spectrometry, significant numbers of naturally processed phosphorylated peptides were detected in association with several human MHC class I molecules. In addition, CD8(+) T cells could be generated that specifically recognized a phosphorylated epitope. Thus, phosphorylated peptides are part of the repertoire of antigens available for recognition by T cells in vivo.

Alleles↗
PubMed1999

Interaction of the nuclear protein CBF1 with the kappaB site of the IL-6 gene promoter.

The nuclear protein CBF1 has been shown to function as an intermediate to target transcription factors,such as the activated Notch receptor,to specific DNA sites. In this paper,we show that CBF1 from cell lines of different origin is able to bind to the[kappa]B site of the IL-6 promoter. By transfection analyses performed in HeLa cells,we demonstrate that overexpressed CBF1 acts as a negative regulator of IL-6 gene transcription and is unable to elicit Notch-dependent activation of this gene. Analyses of protein-DNA interactions indicate that the topology of the complex formed by CBF1 and the target DNA is subtly affected by sequencessurrounding the recognition site. Furthermore,we show that CBF1 induces DNA bending. This finding suggests that CBF1 may influence IL-6 gene transcription by determining a specific conformation of the promoter region.

Base Sequence↗
PubMed2004

GFP-like proteins as ubiquitous metazoan superfamily: evolution of functional features and structural complexity.

Homologs of the green fluorescent protein (GFP), including the recently described GFP-like domains of certain extracellular matrix proteins in Bilaterian organisms, are remarkably similar at the protein structure level, yet they often perform totally unrelated functions, thereby warranting recognition as a superfamily. Here we describe diverse GFP-like proteins from previously undersampled and completely new sources, including hydromedusae and planktonic Copepoda. In hydromedusae, yellow and nonfluorescent purple proteins were found in addition to greens. Notably, the new yellow protein seems to follow exactly the same structural solution to achieving the yellow color of fluorescence as YFP, an engineered yellow-emitting mutant variant of GFP. The addition of these new sequences made it possible to resolve deep-level phylogenetic relationships within the superfamily. Fluorescence (most likely green) must have already existed in the common ancestor of Cnidaria and Bilateria, and therefore GFP-like proteins may be responsible for fluorescence and/or coloration in virtually any animal. At least 15 color diversification events can be inferred following the maximum parsimony principle in Cnidaria. Origination of red fluorescence and nonfluorescent purple-blue colors on several independent occasions provides a remarkable example of convergent evolution of complex features at the molecular level.

Animals↗